Sanjeewa S. Wickremasinghe

Anti-VEGF treatment in neovascular age-related macular degeneration: a treat-and-extend protocol over 2 years.

Purpose: To evaluate 2-year visual acuity outcome of a treat-and-extend protocol of anti–vascular endothelial growth factor treatment in age-related macular degeneration. Methods: In this prospective cohort study, 120 age-related macular degeneration patients with choroidal neovascularization received 3 initial monthly ranibizumab or bevacizumab injections; monthly injections were continued until there was no choroidal neovascularization activity (subretinal/intraretinal fluid, loss of >5 letters, or persistent/recurrent retinal hemorrhage). When there was no choroidal neovascularization activity, the interval to the next visit/injection was extended by 2 weeks to a maximum of 12 weeks. In the presence of choroidal neovascularization activity, this interval was shortened by 2 weeks. Main outcome measures included the percentage losing <15 letters and the mean visual acuity change after 12 months and 24 months. Results: Mean baseline visual acuity was 51.2 ± 12.1 Early Treatment Diabetic Retinopathy Study scores. Mean visual acuity change from baseline was +9.5 ± 10.9 and +8.0 ± 12.9 letters after 12 months and 24 months, respectively, with, on average, 8.6 ± 1.1 visits/injections in the first year and 5.6 ± 2.0 in the second year. After 12 months and 24 months, 97.5% and 95.0% of patients, respectively, lost <15 letters. Conclusion: The “inject-and-extend” protocol—with fewer injections and visits—delivered outcomes comparable to those of the pivotal clinical trials of monthly ranibizumab.

Predictors of anti-VEGF treatment response in neovascular age-related macular degeneration

Currently available evidence on predictors of anti-vascular endothelial growth factor (VEGF) treatment response in neovascular age-related macular degeneration was reviewed. No meta-analysis of results is possible because of a lack of controlled and randomized trials, varying treatment regimes and outcome measures used, as well as suboptimal reporting. For genetic factors, most evidence to date has been generated for single nucleotide polymorphisms (SNPs) in the complement factor H (CFH), and VEGF-A genes. Just under half of the SNPs assessed in the CFH gene and 15% of the SNPs assessed in the VEGF gene were found to be associated with visual outcomes or the number of injections required during follow-up. Some evidence suggests association of worse treatment outcomes as well as a younger age at treatment onset with an increasing number of risk alleles in known risk genes (CFH and ARMS2/HTRA1) and polymorphisms in the VEGF-A gene. Clinical factors such as higher age, a better visual acuity (VA), a larger choroidal neovascularization (CNV) lesion at baseline, and a delay between symptom onset and initiation of treatment of more than 3 weeks also impact outcomes. Conversely, a worse acuity at baseline predicted more gain in vision. Overall, patients presenting with good acuity at baseline were more likely to have good VA at follow up, but the gain afforded by treatment was impacted by a ceiling effect. Most available evidence suggests a strong association of clinical factors such as age, baseline VA, and CNV lesion size with anti-VEGF treatment outcomes. No behavioral factors such as smoking influence treatment outcomes. Based on the studies conducted so far, the evidence suggests that underlying genotype of known AMD risk associated genes or of the VEGF-A gene have a limited effect, whereas presenting clinical factors appear to be more important in determining treatment outcomes.

Variants in the VEGFA Gene and Treatment Outcome after Anti-VEGF Treatment for Neovascular Age-related Macular Degeneration

PURPOSE To determine the association of genetic variants of the VEGFA gene with outcome of anti-vascular endothelial growth factor (VEGF) treatment in neovascular age-related macular degeneration (AMD). DESIGN A prospective cohort study. PARTICIPANTS We included 201 consecutive patients receiving anti-VEGF injections for neovascular AMD. METHODS Patients were followed over 12 months. They were treated with 3 initial monthly ranibizumab or bevacizumab injections. Thereafter, the decision to retreat was made by clinicians at each follow-up visit on the basis of retreatment criteria. Seven tagged single nucleotide polymorphisms (tSNPs) in the VEGFA gene were selected and examined. Multivariate data analysis was used to determine the role of each tSNP in treatment outcome. MAIN OUTCOME MEASURES The influence of selected VEGFA tSNPs on visual acuity (VA) outcome at 6 months. RESULTS Mean baseline VA was 51±17 Early Treatment Diabetic Retinopathy Study (ETDRS) letter scores. Overall, the mean change in VA from baseline was +6.5±12, +4.4±13.4, and +2.3±14.6 letters at 3, 6, and 12 months, respectively. The tSNP rs3025000 was the only SNP significantly associated (P<1 × 10(-4)) with visual outcome at 6 months with multiple correction. The presence of the T allele (TC or TT genotypes) at this tSNP predicted a better outcome of +7 letters at 6 months compared with the CC genotype. In a subgroup analysis, presence of the T allele predicted a significantly higher chance of the patients belonging to the responder group (gain of ≥5 letters from baseline) after 3, 6, and 12 months treatment (odds ratio, 2.7, 3.5, and 2.4; 95% confidence interval, 1.46-5.07, 1.82-6.71, and 1.27-4.57, respectively) than any other outcome group. CONCLUSIONS Pharmacogenetic association with anti-VEGF treatments may influence the visual outcomes in neovascular AMD. In patients with the T allele in tSNP rs3025000, there was a significantly better visual outcome at 6 months and a greater chance of the patients belonging to the responder group with anti-VEGF treatment at 3, 6, and 12 months. The VA outcomes of patients harboring the T allele at SNP rs3025000 were comparable with those of the pivotal clinical trials but with fewer injections, making the treatment perhaps more cost effective in certain subgroups of patients. FINANCIAL DISCLOSURE(S) The authors have no proprietary or commercial interest in any of the materials discussed in this article.

Variants in the APOE Gene Are Associated with Improved Outcome after Anti-VEGF Treatment for Neovascular AMD

PURPOSE Anti-vascular endothelial growth factor (anti-VEGF) drugs have dramatically improved the treatment of neovascular AMD. In pivotal studies, almost 90% of patients maintain vision, with approximately 30% showing significant improvement. Despite these successes, 10% to 15% of patients continue to lose vision, even with treatment. It has been reported that variants in some AMD-associated genes influence treatment outcome. This study showed an association of treatment outcome with variants in the apolipoprotein E (APOE) gene. METHODS One hundred ninety-two patients receiving anti-VEGF treatment for subfoveal choroidal neovascularization secondary to AMD were enrolled. Information on demographics, lesion characteristics, delay until treatment, visual acuity (VA), and number of treatments was collected, and variants of APOE were assessed in all patients at baseline. Best corrected logarithm of the minimum angle of resolution (logMAR) VA was recorded in all patients. RESULTS The presence of the APOE ε4 allele was associated with improved treatment outcome at 3 (P = 0.02) and 12 (P = 0.06) months, compared with the presence of the ε2 allele, after adjustment for baseline acuity, treatment delay after first symptoms, age, and sex. Patients with an APOE ε4 allele had an odds ratio (OR) of 4.04 (95% confidence interval [CI], 1.11-14.70) for a 2-line gain in vision from baseline at 3 months (P = 0.03) and an OR of 2.54 (95% CI, 0.61-10.52; P = 0.20) at 12 months after treatment, based on multivariate analysis. CONCLUSIONS In patients with neovascular AMD, the presence of the APOE ε4 allele conferred significantly better visual outcomes after anti-VEGF treatment than did the ε2 allele. These findings suggest a possible role for a personalized approach to treatment with anti-VEGF.

Syphilitic Punctate Inner Retinitis in Immunocompetent Gay Men

PURPOSE To describe the features of an unusual syphilitic uveitis syndrome in a cluster of homosexual patients. DESIGN Retrospective case series. PARTICIPANTS Five consecutive patients diagnosed with syphilitic retinitis in our Melbourne uveitis clinic over a period of 8 months. METHODS The case notes of patients diagnosed with syphilitic retinitis were reviewed and the clinical features are presented and discussed. MAIN OUTCOME MEASURES Description of retinal findings and documentation of any associated sequelae. RESULTS All patients were homosexual men. Two were human immunodeficiency virus positive. None of the patients had been previously diagnosed with syphilis, although 3 presented with systemic symptoms and signs of secondary syphilis. All patients had marked anterior uveitis and vitritis. All patients had acute retinal arteriolitis and inner retinitis, with distinctive, inner retinal and preretinal white dots. These retinal findings were remarkably similar in all patients, and resolved with little or no sequelae after standard systemic treatment for syphilis, combined with oral prednisolone. CONCLUSIONS Syphilitic retinitis may be an increasingly common clinical problem, reflecting the growing incidence of syphilis among homosexual men in Australia. Our patients showed stereotypical ocular and systemic features, which are useful in differentiating this condition clinically from other types of acute posterior uveitis, such as necrotizing viral retinitis. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

The prevalence estimates of macular telangiectasia type 2: the Melbourne Collaborative Cohort Study.

Purpose: The purpose of this study was to determine the prevalence estimates of macular telangiectasia type 2 in an Australian population based on nonmydriatic digital fundus photography. Methods: Participants of the Melbourne Collaborative Cohort Study, initiated to investigate risk factors for common aging diseases, had nonmydriatic digital macular images taken from both eyes and graded for any macular abnormalities. Prevalence of the features suggestive of macular telangiectasia type 2 was assessed. Results: Macular images from the 22,062 subjects with a mean age of 64.96 years (range, 47–85 years) were assessed. Of these images, 43,234 images were gradable (21,708 images of the right eye and 21,526 images of the left eye). Using only the grading features of the macular images taken by the nonmydriatic digital fundus photography, 5 subjects with signs consistent with bilateral macular telangiectasia type 2 in this population were found by the authors. Based on the Gass-Blodi staging of this disease, all (5) were determined to be in stages 2 and 3. Conclusion: In an Australian population, the prevalence estimates of macular telangiectasia type 2 were found to be 1 of 22,062 to 5 of 22,062 or 5 to 23 cases per 100,000 people in which disease was at least at stages 2 and 3.

Retinal Vascular Caliber Changes after Intravitreal Triamcinolone Treatment for Diabetic Macular Edema

PURPOSE To describe the changes in retinal vascular caliber in response to a single injection of intravitreal triamcinolone (IVTA) in patients with refractory diabetic macular edema. METHODS Prospective data from a randomized clinical trial were used. The effects of IVTA versus sham injections in patients with refractory diabetic macular edema were evaluated in a randomized clinical trial involving 69 eyes of 43 patients. Of these, 28 eyes (15 IVTA and 13 sham) of 21 patients had gradable retinal photographs at the baseline and 3-month follow-up visit for analysis in the present study. Retinal vascular caliber was measured from digital fundus photographs and summarized as central retinal artery (CRAE) and vein (CRVE) equivalents in all eyes at baseline and at the 3-month follow-up visit. RESULTS Over the 3 months of the study, there was a significant reduction compared to baseline in retinal arteriolar (147.8 microm vs. 140.0 microm, P = 0.047) and venular (219.5 microm vs. 198 microm, P = 0.039) caliber in eyes treated with IVTA. There was no change in retinal arteriolar (139.9 microm vs. 139.2 microm, P = 0.878) or venular (220.3 microm vs. 217.6 microm, P = 0.534) caliber in those treated with sham injections. CONCLUSIONS IVTA has a significant narrowing effect on both retinal arteriolar and venular diameter in eyes with diabetic macular edema (ClinicalTrials.gov number, NCT00148330).

Ranibizumab treatment for neovascular age-related macular degeneration: from randomized trials to clinical practice

BackgroundAlthough randomized clinical trials (ANCHOR and MARINA) have shown excellent results of ranibizumab treatment in patients with neovascular age-related macular degeneration (AMD), it is unclear whether such an outcome is achievable in daily practice. We evaluated the results of ranibizumab treatment for neovascular AMD in clinical practice in Australia.MethodsA retrospective chart review of patients in four practices injected with ranibizumab in 2006 for AMD. Patients who had been diagnosed with subfoveal choroidal neovascular membrane in the preceding 6 months and had completed at least 6 months follow-up were enrolled. No standard treatment protocols were required. The main outcome measure was visual acuity (VA) at 6 and 12 months.ResultsA total of 158 patients fulfilled the entry criteria. The mean baseline VA (decimal) was 0.35±0.21 (Snellen equivalent 6/17). At 6 months, the mean VA improved to 0.46±0.27 (6/13) and remained stable until month 12 (0.48±0.30). The improvement in VA between baseline and months 6 and 12 was statistically significant (P<0.0001). Both the mean and the median number of injections were four in the first 6 months and nine at 12 months. VA results were comparable with those of the ANCHOR and MARINA trials, and were achieved with a lower number of injections (P<0.0001).ConclusionVA results achieved in daily clinical practice using ranibizumab for neovascular AMD are similar to large prospective randomized trials.

Retinal Venular Caliber Predicts Visual Outcome after Intravitreal Ranibizumab Injection Treatments for Neovascular AMD

PURPOSE To examine whether baseline retinal vascular caliber predicts visual response to intravitreal ranibizumab injections in patients with neovascular age-related macular degeneration (AMD). METHODS In this prospective cohort study, patients with neovascular AMD received three monthly intravitreal injections of ranibizumab, followed by as needed dosing up to 1 year. Retinal vascular caliber was measured from digital fundus photographs at baseline and summarized as central retinal artery equivalent (CRAE) and venular equivalent (CRVE), representing average caliber of arterioles and venules, respectively. Visual outcome at 12 months was assessed and the relation to baseline retinal vascular caliber was determined. RESULTS A total of 88 eyes were analyzed at baseline. After accounting for age, sex, size of choroidal neovascularization, and number of injections, patients who deteriorated in visual acuity at 12 months had significantly larger baseline CRVE, 243.10 μm (95% confidence interval [CI], 227.01-259.19), compared with those who were stable, 214.30 μm (95% CI, 205.79-222.81) and those who improved, 215.26 μm (95% CI, 204.69-225.84; P = 0.007). Baseline CRAE did not differ significantly from eyes whose vision deteriorated, 150.12 μm (95% CI, 140.67-159.57), compared with those remaining stable, 143.64 μm (95% CI, 138.64-148.63), or gaining vision 142.92 μm (95% CI, 136.71-149.13; P = 0.69). CONCLUSIONS In eyes with neovascular AMD treated with intravitreal ranibizumab, larger baseline retinal venular caliber was significantly associated with a poorer response to treatment, possibly reflecting increased disease severity.

A comparison of HRT II and GDx imaging for glaucoma detection in a primary care eye clinic setting.

PurposeTo evaluate the performance of the HRT II (Heidelberg retinal tomograph) and GDx (glaucoma detection) retinal nerve fibre analyzer in GDx when used in the primary care eye clinic setting for glaucoma screening.Patients and MethodsThe study was prospective, cross-sectional, and hospital-based. One-hundred and twelve patients, 59 women and 53 men with a mean age of 57.8 years (range 18–85 years), had consecutive HRT II disc imaging and GDx retinal nerve fiber layer analysis. The Moorfields regression classification and the ‘GDx number’ were used to predict the likelihood of glaucoma. A separate clinician, masked to the instrument results determined a definitive diagnosis, based on clinical examination. The extent of agreement between instrument prediction and the clinician diagnosis of glaucoma was examined by generating sensitivity and specificity tables.ResultsThe HRT II had a sensitivity of 0.79 (95% CI: 0.60–0.92) and a specificity of 0.70 (95% CI: 0.60–0.78). The positive predictive value of the HRT II was 0.43 (95% CI: 0.29–0.57). Using a GDx number of 50 as ‘cutoff’ for glaucoma detection, the GDx had a sensitivity of 0.80 (95% CI: 0.59–0.93) and a specificity of 0.72 (95% CI: 0.61–0.80), with a positive predictive value of 0.43 (95% CI: 0.28–0.59).ConclusionsFor glaucoma detection, neither the HRT II nor the GDx are effective as stand-alone screening devices in the primary care setting.