Catherine B. Meyerle

Intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration.

Purpose: To describe the short-term anatomical and visual acuity responses after intravitreal injection of bevacizumab (Avastin, Genentech) in patients with choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). Methods: We conducted a retrospective study of patients with CNV secondary to AMD who were treated with intravitreal injection of bevacizumab (1.25 mg) during a 3-month period. Patients underwent best-corrected Snellen visual acuity testing, optical coherence tomography, and ophthalmoscopic examination at baseline and follow-up visits. Results: There were 266 consecutive eyes of 266 patients who received injections, and follow-up information was available for 251 (94.4%). The mean age of the patients was 80.3 years, the mean baseline visual acuity was 20/184, and 175 (69.7%) had inadequate response to alternate methods of treatment. At the 1-month follow-up (data available for 244 patients), the mean visual acuity was 20/137 (P < 0.001 as compared with baseline), and 74 (30.3%) of patients had improvement in visual acuity as defined by a halving of the visual angle. At the 2-month follow-up (data available for 222 patients), the mean visual acuity was 20/122 (P < 0.001), and 78 (31.1%) of patients had visual improvement. At the 3-month follow-up (data available for 141 patients), the mean visual acuity was 20/109 (P < 0.001), and 54 (38.3%) of patients had visual acuity improvement. The mean central macular thickness at baseline was 340 &mgr;m and decreased to a mean of 247 &mgr;m at month 1 (P < 0.001) and 213 &mgr;m at month 3 (P < 0.001). At 1 month, two patients had mild vitritis, as did one patient at 2 months, who had a history of recurrent uveitis. No endophthalmitis, increased intraocular pressure, retinal tear, or retinal detachment occurred. The risk for thromboembolic disorders did not seem to be different than reported previously in studies concerning macular degeneration. Conclusion: There were no apparent short-term safety concerns for intravitreal bevacizumab injection for CNV. Treated eyes had a significant decrease in macular thickness and improvement in visual acuity. The follow-up was too short to make any specific treatment recommendations, but the favorable short-term results suggest further study is needed.

Intravitreal bevacizumab (Avastin) treatment of macular edema in central retinal vein occlusion: a short-term study.

Purpose: To report the short term anatomic and visual acuity response after intravitreal injection of bevacizumab (Avastin, Genentech) in patients with macular edema due to central retinal vein occlusion (CRVO). Methods: The authors conducted a retrospective study of patients with macular edema due to CRVO who were treated with at least one intravitreal injection of bevacizumab 1.25 mg in 0.05 mL. Patients underwent Snellen visual acuity testing, optical coherence tomography (OCT) imaging, and ophthalmoscopic examination at baseline and follow-up visits. Results: There were 16 eyes of 15 consecutive patients with a mean age of 76.1 years (SD 9.8 years). Intravitreal triamcinolone had been previously administered to 9 patients, but all of these patients either had no improvement or had excessive intraocular pressure caused by the triamcinolone. The patients received a mean of 2.8 injections of bevacizumab per eye. No adverse events were observed, including endophthalmitis, clinically evident inflammation, increased intraocular pressure, retinal tears, retinal detachment, or thromboembolic events in any patient. The mean central macular thickness at baseline was 887 &mgr;m and decreased to a mean of 372 &mgr;m at month 1 (P < 0.001). The mean baseline acuity was 20/600 (logMAR = 1.48) and the mean acuity at month 1 was 20/200 (logMAR = 1.05), a difference that was highly significant (P = 0.001). At last follow-up, a mean of 3 months after the first injection, the mean visual acuity was 20/138 (logMAR = 0.84), which was significantly better than baseline (P < 0.001). Visual acuity improvement, defined as a halving of the visual angle, was seen in 14 of the 16 eyes. Conclusion: Initial treatment results of patients with macular edema secondary to CRVO did not reveal any short-term safety concerns. Intravitreal bevacizumab resulted in a significant decrease in macular edema and improvement in visual acuity. The number of patients in this pilot study was limited and the follow-up is too short to make any specific treatment recommendations, but the favorable short-term results suggest further study is needed.

Central Serous Chorioretinopathy: Update on Pathophysiology and Treatment

Recent technological advances--new pathophysiological insights, new imaging techniques for diagnosis and management, and new treatments--have led to an improved understanding of central serous chorioretinopathy (CSC). The primary role of the choroid has become more widely accepted with widespread use of indocyanine green angiography. Optical coherence tomography (OCT), and particularly enhanced depth imaging OCT, demonstrate a thickened and engorged choroid. Adaptive optics, fundus autofluorescence, multifocal electroretinography, microperimetry, and contrast sensitivity testing reveal that patients with even a mild course suffer previously undetected anatomic and functional loss. Although focal laser and photodynamic therapy are the current standard of care for persistent subretinal fluid in CSC, they are not appropriate in all cases, and the optimal timing of intervention remains unclear.

Evaluation of time domain and spectral domain optical coherence tomography in the measurement of diabetic macular edema

PURPOSE To evaluate macular thickness and volume measurements and their intrasession repeatability in two optical coherence tomography (OCT) systems: the Stratus OCT, a time domain system, and the Cirrus HD-OCT, a spectral domain system (both by Carl Zeiss Meditec, Inc., Dublin, CA), in the context of diabetic macular edema (DME). METHODS Thirty-three eyes of 33 diabetic patients with clinically significant macular edema (CSME) were scanned in a single session by a single operator on both OCT systems. Macular thickness measurements of nine standard macular subfields and total macular volume were obtained and analyzed. Bland-Altman plots were constructed to assess agreement in macular measurements. Intraclass correlation coefficients (ICCs), coefficients of repeatability (CR(W)), and coefficients of variation (CV(W)) were used to assess intrasession repeatability. RESULTS Macular thickness in nine retinal subfields and macular volume were significantly higher in the Cirrus HD-OCT system compared with the Stratus OCT system. Subfield thickness and total volume measurements, respectively, were 30 to 55 microm and 3.2 mm(3) greater for the Cirrus HD-OCT system compared with the Stratus OCT system. Both Stratus OCT and Cirrus HD-OCT systems demonstrated high intrasession repeatability, with overlapping ranges for CR(W), CV(W), and ICC. Repeatability measures (CR(W) and CV(W)) differed significantly between systems in only one of nine subfields (outer temporal subfield). CONCLUSIONS Absolute measures of macular thickness and volume in patients with DME differed significantly in magnitude between the Stratus OCT and Cirrus HD-OCT systems. However, both OCT systems demonstrated high intrasessional repeatability. Although the two systems may not be used interchangeably, they appear equally reliable in generating macular measurements for clinical practice and research.

Tachyphylaxis after intravitreal bevacizumab for exudative age-related macular degeneration.

Purpose: To describe tachyphylaxis to intravitreal bevacizumab (IVB) in patients with exudative age-related macular degeneration (AMD). Methods: We retrospectively reviewed the records of 59 consecutive patients treated with IVB at the National Eye Institute over a 14-month period and identified cases demonstrating loss of treatment efficacy as revealed by spectral domain optical coherence tomography. We defined tachyphylaxis as a loss of therapeutic response to IVB 28 ± 7 days after administration in an eye that had previously demonstrated a therapeutic response in the same time interval. Results: Five patients (six eyes) were identified as developing tachyphylaxis after repeated treatment with IVB. High-dose IVB (2.50 mg) did not restore therapeutic response in these patients. Bilateral tachyphylaxis to IVB was seen after an episode of unilateral postinjection anterior uveitis. After the first treatment of IVB, the median time taken to develop tachyphylaxis was 100 weeks (range: 31–128 weeks), and the median number of IVB treatments to the development of tachyphylaxis was 8 treatments (range: 5–10 treatments). Conclusion: Tachyphylaxis can occur after long-term intravitreal use of bevacizumab in patients with AMD. The precise mechanism of tachyphylaxis is unclear, but both local and/or systemic factors may be involved.

Complement component C5a Promotes Expression of IL-22 and IL-17 from Human T cells and its Implication in Age-related Macular Degeneration

BackgroundAge related macular degeneration (AMD) is the leading cause of irreversible blindness in elderly populations worldwide. Inflammation, among many factors, has been suggested to play an important role in AMD pathogenesis. Recent studies have demonstrated a strong genetic association between AMD and complement factor H (CFH), the down-regulatory factor of complement activation. Elevated levels of complement activating molecules including complement component 5a (C5a) have been found in the serum of AMD patients. Our aim is to study whether C5a can impact human T cells and its implication in AMD.MethodsHuman peripheral blood mononuclear cells (PBMCs) were isolated from the blood of exudative form of AMD patients using a Ficoll gradient centrifugation protocol. Intracellular staining and enzyme-linked immunosorbent assays were used to measure protein expression. Apoptotic cells were detected by staining of cells with the annexin-V and TUNEL technology and analyzed by a FACS Caliber flow cytometer. SNP genotyping was analyzed by TaqMan genotyping assay using the Real-time PCR system 7500.ResultsWe show that C5a promotes interleukin (IL)-22 and IL-17 expression by human CD4+ T cells. This effect is dependent on B7, IL-1β and IL-6 expression from monocytes. We have also found that C5a could protect human CD4+ cells from undergoing apoptosis. Importantly, consistent with a role of C5a in promoting IL-22 and IL-17 expression, significant elevation in IL-22 and IL-17 levels was found in AMD patients as compared to non-AMD controls.ConclusionsOur results support the notion that C5a may be one of the factors contributing to the elevated serum IL-22 and IL-17 levels in AMD patients. The possible involvement of IL-22 and IL-17 in the inflammation that contributes to AMD may herald a new approach to treat AMD.

Hypomethylation of the IL17RC promoter associates with age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly population worldwide. Although recent studies have demonstrated strong genetic associations between AMD and SNPs in a number of genes, other modes of regulation are also likely to play a role in the etiology of this disease. We identified a significantly decreased level of methylation on the IL17RC promoter in AMD patients. Furthermore, we showed that hypomethylation of the IL17RC promoter in AMD patients led to an elevated expression of its protein and messenger RNA in peripheral blood as well as in the affected retina and choroid, suggesting that the DNA methylation pattern and expression of IL17RC may potentially serve as a biomarker for the diagnosis of AMD and likely plays a role in disease pathogenesis.

Intravitreal Bevacizumab (avastin) For Retinal Angiomatous Proliferation

Objective: To evaluate the short-term visual acuity and anatomic responses after intravitreal bevacizumab (Avastin, Genentech) treatment in patients with retinal angiomatous proliferation (RAP). Methods: The authors conducted a retrospective review of consecutive patients with newly diagnosed or recurrent RAP treated with intravitreal bevacizumab (1.25 mg) during a 3-month period. Complete ocular examination was performed at baseline and follow-up visits. Interval data were analyzed statistically at 1 and 3 months follow-up. Results: Twenty-three eyes of 23 patients underwent intravitreal bevacizumab treatment. The mean age of patients was 81.1 years, median baseline visual acuity of treated eyes was 20/80 (range 20/25–20/800), and mean baseline central macular thickness was 335 &mgr;m (optical coherence tomography was available for 22 eyes). Nine eyes had retinal pigment epithelial detachments (PEDs) at baseline. At 1-month follow-up, the median acuity improved to 20/60 (range 20/30–20/400) (P < 0.001), mean central macular thickness decreased to 202 &mgr;m (P < 0.001), and PED was present in only 2 eyes (P = 0.016). Seven of 23 eyes at 1 month (30.4%) had improved visual acuity, defined as halving of the visual angle, and no eyes had worse acuity, defined as doubling of the visual angle. Of the 17 eyes available for 3-month follow-up, 5 eyes (29.4%) had better visual acuity, 1 eye (5.9%) had worse acuity, and the remaining 11 (64.7%) had the same acuity. The median visual acuity at month 3 was 20/60 (range 20/25–20/400). There were no thromboembolic phenomena, endophthalmitis cases, retinal detachments, or any other adverse events. Conclusion: Treatment of RAP with intravitreal bevacizumab during this retrospective review resulted in a significant decrease in macular thickness and improvement or stabilization of visual acuity. Further long-term investigation is warranted given the promising short-term results.

Relationship between Photoreceptor Outer Segment Length and Visual Acuity in Diabetic Macular Edema

Purpose: The purpose of this study was to quantify photoreceptor outer segment (PROS) length in 27 consecutive patients (30 eyes) with diabetic macular edema using spectral domain optical coherence tomography and to describe the correlation between PROS length and visual acuity. Methods: Three spectral domain–optical coherence tomography scans were performed on all eyes during each session using Cirrus HD-OCT. A prototype algorithm was developed for quantitative assessment of PROS length. Retinal thicknesses and PROS lengths were calculated for 3 parameters: macular grid (6 × 6 mm), central subfield (1 mm), and center foveal point (0.33 mm). Intrasession repeatability was assessed using coefficient of variation and intraclass correlation coefficient. The association between retinal thickness and PROS length with visual acuity was assessed using linear regression and Pearson correlation analyses. The main outcome measures include intrasession repeatability of macular parameters and correlation of these parameters with visual acuity. Results: Mean retinal thickness and PROS length were 298 μm to 381 μm and 30 μm to 32 μm, respectively, for macular parameters assessed in this study. Coefficient of variation values were 0.75% to 4.13% for retinal thickness and 1.97% to 14.01% for PROS length. Intraclass correlation coefficient values were 0.96 to 0.99 and 0.73 to 0.98 for retinal thickness and PROS length, respectively. Slopes from linear regression analyses assessing the association of retinal thickness and visual acuity were not significantly different from 0 (P > 0.20), whereas the slopes of PROS length and visual acuity were significantly different from 0 (P < 0.0005). Correlation coefficients for macular thickness and visual acuity ranged from 0.13 to 0.22, whereas coefficients for PROS length and visual acuity ranged from −0.61 to −0.81. Conclusion: Photoreceptor outer segment length can be quantitatively assessed using Cirrus HD-OCT. Although the intrasession repeatability of PROS measurements was less than that of macular thickness measurements, the stronger correlation of PROS length with visual acuity suggests that the PROS measures may be more directly related to visual function. Photoreceptor outer segment length may be a useful physiologic outcome measure, both clinically and as a direct assessment of treatment effects.

Treatment of Geographic Atrophy by the Topical Administration of OT-551: Results of a Phase II Clinical Trial

PURPOSE To investigate the safety and preliminary efficacy of OT-551, a disubstituted hydroxylamine with antioxidant properties, for the treatment of geographic atrophy (GA), the advanced atrophic form of age-related macular degeneration (AMD). METHODS The study was a single-center, open-label phase II trial, enrolling 10 participants with bilateral GA. Topical 0.45% OT-551 was administered in one randomly assigned eye three times daily for 2 years. Safety measures were assessed by complete ophthalmic examination, fundus photography, and review of symptoms. The primary efficacy outcome measure was the change in best corrected visual acuity at 24 months. Secondary efficacy measures included changes in area of GA, contrast sensitivity, microperimetry measurements, and total drusen area from baseline. RESULTS Study drug was well tolerated and was associated with few adverse events. The mean change in BCVA at 2 years was +0.2 ± 13.3 letters in the study eyes and -11.3 ± 7.6 letters in fellow eyes (P = 0.0259). However, no statistically significant differences were found between the study and fellow eyes for all other secondary outcome measures. CONCLUSIONS OT-551 was well tolerated by study participants and was not associated with any serious adverse effects. Efficacy measurements in this small study indicate a possible effect in maintaining visual acuity. However, the absence of significant effects on other outcomes measures in this study suggests that OT-551, in the current concentration and mode of delivery, may have limited or no benefit as a treatment for GA (ClinicalTrials.gov number, NCT00306488).