Seenu M. Hariprasad

Sustained Delivery Fluocinolone Acetonide Vitreous Inserts Provide Benefit for at Least 3 Years in Patients with Diabetic Macular Edema

OBJECTIVE To assess long-term efficacy and safety of intravitreal inserts releasing 0.2 μg/d (low dose) or 0.5 μg/d (high dose) fluocinolone acetonide (FAc) in patients with diabetic macular edema (DME). DESIGN Two randomized, sham injection-controlled, double-masked, multicenter clinical trials. PARTICIPANTS Subjects with persistent DME despite ≥1 macular laser treatment were randomized 1:2:2 to sham injection (n = 185), low-dose insert (n = 375), or high-dose insert (n = 393). METHODS Subjects received study drug or sham injection and after 6 weeks were eligible for rescue laser. Based on retreatment criteria, additional study drug or sham injections could be given after 1 year. MAIN OUTCOME MEASURES Percentage of patients with improvement of ≥15 letters from baseline. Secondary outcomes included other parameters of visual function and foveal thickness. RESULTS At month 36, the percentage of patients who gained ≥15 in letter score using the last observation carried forward method was 28.7% (low dose) and 27.8% (high dose) in the FAc insert groups compared with 18.9% (P = 0.018) in the sham group, and considering only those patients still in the trial at month 36, it was 33.0% (low dose) and 31.9% (high dose) compared with 21.4% in the sham group (P = 0.030). Preplanned subgroup analysis demonstrated a doubling of benefit compared with sham injections in patients who reported duration of DME ≥3 years at baseline; the percentage who gained ≥15 in letter score at month 36 was 34.0% (low dose; P<0.001) or 28.8% (high dose; P = 0.002) compared with 13.4% (sham). An improvement ≥2 steps in the Early Treatment Diabetic Retinopathy Study retinopathy scale occurred in 13.7% (low dose) and 10.1% (high dose) compared with 8.9% in the sham group. Almost all phakic patients in the FAc insert groups developed cataract, but their visual benefit after cataract surgery was similar to that in pseudophakic patients. The incidence of incisional glaucoma surgery at month 36 was 4.8% in the low-dose group and 8.1% in the high-dose insert group. CONCLUSIONS In patients with DME FAc inserts provide substantial visual benefit for up to 3 years and would provide a valuable addition to the options available for patients with DME.

Voriconazole in the treatment of fungal eye infections: a review of current literature

Background: Voriconazole has an important role to play in the prophylaxis and management of fungal endophthalmitis and keratitis. New-generation triazoles, including voriconazole, posaconazole and ravuconazole, have been shown in laboratory studies and clinical experience to have very good safety profiles with few side effects. Fungal eye infections, while not common in temperate climates, have been notoriously difficult to diagnose and treat, and generally result in protracted therapy with poor final outcomes. Current treatment options are far from optimal. Aims: This paper will review studies and clinical case reports published in the ophthalmic literature that address the safety of these drugs in the eye, penetration and concentration in ocular tissues and media, and efficacy in treating common pathogens implicated in fungal keratitis and endophthalmitis. Conclusions: Over 40 clinical case reports of treatment with voriconazole suggest that it may be used safely and effectively against a broad range of fungal pathogens.

Prospective Comparison of Cirrus and Stratus Optical Coherence Tomography for Quantifying Retinal Thickness

PURPOSE To compare Cirrus Fourier-domain optical coherence tomography (OCT) with Stratus time-domain OCT for imaging retinal diseases and quantifying retinal thickness (RT) of all nine OCT zones, central macular thickness, and average macular thickness in eyes with and without macular edema. DESIGN Prospective comparison between two OCT systems. METHODS RT measurements were performed in 120 eyes of 60 patients suspected of having increased retina thickness using both Stratus and Cirrus OCT on the same day. Twenty-one eyes had both 512 x 128 and 200 x 200 Cirrus cube scans done. RESULTS Data from 101 eyes (53 patients) were analyzed; 46 eyes (45.5%) had macular edema on clinical examination (Group 1), whereas 55 eyes (54.4%) had no clinical evidence of macular edema (Group 2). There was modest correlation between all thickness measurements in 909 zones and each group (range of Pearson correlation, 0.51 to 0.89) and average value was significantly greater when measured with Cirrus OCT for all eyes (mean difference, 43.2 microm; P < .0001). There were few measurement differences between different resolution Cirrus cube scans. CONCLUSIONS Cirrus OCT measures RT approximately 43 microm greater than Stratus OCT, which is likely attributable to Cirrus OCT detection of the outer band of the retinal pigment epithelium vs Stratus OCT detection of the inner/outer segment photoreceptor junction. All zones showed a wide degree of variability in correlation. Both Cirrus cube scans provide similar data. Future studies comparing these systems might consider utilizing average macular thickness values, which reflect macular volume and may provide more consistent measurements.

A phase I study of intravitreal vascular endothelial growth factor trap-eye in patients with neovascular age-related macular degeneration.

PURPOSE To determine the safety, tolerability, maximum tolerated dose, and bioactivity of an intravitreal injection of vascular endothelial growth factor (VEGF) Trap-Eye, a fusion protein of binding domains from human VEGF receptors 1 and 2 with human immunoglobulin-G Fc that binds VEGF family members, in patients with neovascular age-related macular degeneration (AMD). DESIGN Dose-escalation, multicenter, interventional clinical trial. PARTICIPANTS Twenty-one patients (13 female, 8 male) with neovascular AMD (NVAMD) and lesions <or=12 disc areas in size and >or=50% active choroidal neovascularization (CNV) with best-corrected visual acuity (BCVA) <or=20/40 received a single intraocular injection of 0.05 mg (n = 3), 0.15 mg (n = 3), 0.5 mg (n = 3), 1 mg (n = 6), 2 mg (n = 3), or 4 mg (n = 3) of VEGF Trap-Eye. METHODS Safety assessments included eye examinations, vital signs, and laboratory tests. Measures of bioactivity included changes from baseline in BCVA, optical coherence tomography (OCT), and fluorescein angiography. The primary end point was 6 weeks and patients were followed up for 12 weeks. MAIN OUTCOME MEASURE Safety assessments. RESULTS There were no serious adverse events and no identifiable intraocular inflammation. The mean decrease in excess foveal thickness for all patients was 104.5 mum at 6 weeks, and the mean increase in visual acuity was 4.43 letters. In the 2 highest dose groups combined (2 and 4 mg), the mean increase in BCVA was 13.5 letters, with 3 of 6 patients demonstrating improvement of >or=3 lines and 3 patients requiring no adjunctive treatment of any type for 12 weeks. Some showed elimination of fluorescein leakage and reduction in area of CNV. CONCLUSIONS Intravitreal injection of up to 4 mg of VEGF Trap-Eye in patients with NVAMD was well tolerated with no evidence of ocular inflammation. Although the number of patients in each cohort was small, there was evidence of bioactivity, because several patients, especially those receiving 2 or 4 mg of VEGF Trap-Eye, showed substantial improvement in BCVA associated with reductions in foveal thickness. Phase III trials to investigate the efficacy of intraocular VEGF Trap-Eye in patients with NVAMD are under way.

Vision-related quality of life in patients with diabetic macular oedema.

Aims: The aim of this study was to determine the impact of diabetic macular oedema (DME) on the quality of life (QOL) in patients with type 2 diabetes mellitus. Methods: The study was a prospective, consecutive, non-comparative case series. An observational study evaluated the quality of vision and vision-specific QOL using the 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25). Mean VFQ-25 subscale scores in type 2 diabetic study patients were compared with mean VFQ-25 subscale score in groups of patients with type 1 diabetic retinopathy (T1DR) and varying degrees of age-related macular degeneration (ARMD), glaucoma and cataracts and in reference populations. Results: Thirty-three patients completed the NEI VFQ-25. The mean age of the study population was 64 years. When performing a comparison of those patients with DME versus those with isolated T1DR we found that for the general health subscale, the DME versus T1DR group means were 42±4.4 versus 61±1.0 respectively. The DME versus T1DR quality of vision categorical mean scores were 69±4.1 versus 93±3.9. The DME versus T1DR VR-QOL categorical mean scores were 62±5.0 versus 93±1.0. The DME group was significantly worse in each of these three categories compared with the T1DR group (p<0.01). An additional analysis was performed to examine the differences in VR-QOL in the DME group versus varying common ocular diseases, including age-related macular degeneration (ARMD), glaucoma, cataracts and disease-free reference groups. The mean values of VFQ-25 subscale in the DME group were significantly lower then the glaucoma group in ten of 12 subscales, the cataract group in 11 of 12 subscales, and the reference group in 12 of 12 subscales. However, the mean values of VFQ-25 subscale in the DME group were only significantly different from the ARMD group in three of 12 subscales. Conclusions: Type 2 diabetes patients with macular oedema experience a decreased VR-QOL compared with type 1 diabetic patients with diabetic retinopathy, glaucoma or cataracts. However, VR-QOL in type 2 diabetic patients with macular oedema was similar to those individuals with ARMD.

Aqueous and Vitreous Concentrations Following Topical Administration of 1% Voriconazole in Humans

OBJECTIVE To determine the penetration of 1% voriconazole solution into the aqueous and vitreous following topical administration. METHODS A prospective nonrandomized study of 13 patients scheduled for pars plana vitrectomy surgery. Aqueous and vitreous samples were obtained and analyzed after topical administration of 1% voriconazole every 2 hours for 24 hours before surgery. Drug concentration quantitation was performed using high-performance liquid chromatography. RESULTS The mean (SD) sampling time after topical administration of the last voriconazole dose was 24 (14) minutes. The mean (SD) voriconazole concentrations in the aqueous and vitreous were 6.49 (3.04) microg/mL and 0.16 (0.08) microg/mL, respectively. Aqueous concentrations exceeded the minimum inhibitory concentration at which 90% of isolates are inhibited (MIC(90)) for a wide spectrum of fungi and mold, including Aspergillus, Fusarium, and Candida species. Vitreous concentrations of voriconazole exceeded the MIC(90) for Candida albicans. CONCLUSION Topically administered voriconazole achieves therapeutic concentrations in the aqueous of the noninflamed human eye for many fungi and molds and achieves therapeutic levels in the vitreous for Candida species. Topical voriconazole may be a useful agent for the management of fungal keratitis and for prophylaxis against the development of fungal endophthalmitis.

Short-term intraocular pressure trends following intravitreal injections of ranibizumab (Lucentis) for the treatment of wet age-related macular degeneration

Rosenfeld and colleagues reported that ranibizumab (Lucentis) had no long-term effect on intraocular pressure (IOP) as determined by monthly measurements during the 2-year MARINA study.1 We are unaware of previous studies examining the short-term effect on IOP by intravitreal ranibizumab in patients with wet age-related macular degeneration. We conducted a retrospective chart review of 50 ranibizumab injections from 23 patients. IOP was recorded using Goldmann applanation tonometry. All patients included in this series received ranibizumab injection as directed by the instructions provided in the package insert (volume …

Review of Ranibizumab Trials for Neovascular Age-Related Macular Degeneration

Ranibizumab, a recombinant, humanized, monoclonal antibody antigen-binding fragment that neutralizes all VEGF-A isoforms, is the first US FDA-approved therapy for neovascular age-related macular degeneration (AMD) to result in improvement in visual acuity. The benefit of intravitreal ranibizumab applies to all angiographic subtypes of neovascular AMD and across all lesion sizes. The two original phase III studies (ANCHOR and MARINA) demonstrated sustained visual acuity (VA) gains over a two-year monthly dosing schedule. Following these trials, several studies looked at ways to decrease the treatment burden while maintaining similar visual gains. These trials included PIER, PrONTO, EXCITE, SUSTAIN, HORIZON, and CATT. Visual acuity data shows that monthly dosing of ranibizumab produces superior vision outcomes compared to a less-frequent, fixed-dosing schedule. Intravitreal ranibizumab is well tolerated and shown to have a very low rate of adverse ocular or systemic side-effects.

The utility of visual function questionnaire in the assessment of the impact of diabetic retinopathy on vision-related quality of life

AimsTo determine whether the Visual Function Questionnaire-25 (VFQ) is a more accurate instrument for assessing vision related quality of life (VRQOL) than visual acuity (VA) in patients with diabetic retinopathy. To compare VRQOL between patients with non-proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR).MethodsWe administered the VFQ and Vision Preference Value Scale (VPVS) to 104 patients. With VPVS as the gold standard in our study, we used Pearsons correlation and multiple linear regression analysis to assess whether VFQ is a more accurate measure of VRQOL than VA. Spearman correlation coefficients were used to assess which VFQ subscales correlated strongly with VPVS. Patients with NPDR and PDR were compared using VFQ.ResultsThe Pearsons correlation coefficient between VPVS and VFQ was 0.49 (P<0.01) and between VPVS and VA was 0.33 (P<0.01). In multivariable linear models, VFQ explained a higher proportion of the variance in VPVS than VA. The VFQ subscales with the strongest Spearman coefficients to VPVS scores were role differences, near activities, distance activities, mental function and dependence. In these subscales, patients with PDR vsNPDR suffered a 25–30 point loss (100-point scale).ConclusionsVFQ is a superior measure of VRQOL for patients with diabetic retinopathy because it better captures mental and emotional aspects of the disease as well as visual function. Subjects with PDR vsNPDR suffer significant loss of VRQOL.

Successful treatment of postoperative fungal endophthalmitis using intravitreal and intracameral voriconazole.

AIM The aim of this study was to describe 3 cases of postoperative fungal endophthalmitis successfully treated with anterior chamber washout, pars plana vitrectomy, and intracameral and intravitreal voriconazole injection. RESULTS Three (3) patients from a single retina center in India developed culture-proven fungal endophthalmitis after cataract surgery in 1 eye. All patients underwent anterior chamber washout, pars plana vitrectomy, and intracameral and intravitreal voriconazole injections intraoperatively. All cases demonstrated substantial improvement in vision and intraocular inflammation after surgery. CONCLUSIONS The combination of anterior chamber washout, pars plana vitrectomy, and intracameral and intravitreal voriconazole injection is a viable therapeutic option in cases of fungal endophthalmitis.