Imaging Biomarkers and Their Impact on Therapeutic Decision-Making in the Management of Neovascular Age-Related Macular Degeneration.

These recommendations, produced by a group of Canadian retina experts, have been developed to assist both retina specialists and general ophthalmologists in the management of vision-threatening neovascular age-related macular degeneration (nAMD). The recommendations are based on published evidence as well as collective experience and expertise in routine clinical practice. We provide an update on practice principles for optimal patient care, focusing on identified imaging biomarkers, in particular retinal fluid, as well as current and emerging therapeutic approaches. Algorithms for delivering high-quality care and improving long-term patient outcomes are provided, with an emphasis on timely and appropriate treatment to preserve and maintain vision. In the context of nAMD, increasing macular fluid or leakage on fluorescein angiography (FA) may indicate disease activity regardless of its location. Early elimination of intraretinal fluid (IRF) is of particular relevance as it is a prognostic indicator of worse visual outcomes. Robust referral pathways for second opinion and peer-to-peer consultations must be in place for cases not responding to intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy.

Effects of intravitreal bevacizumab in Gram-positive and Gram-negative models of ocular inflammation.

BACKGROUND: Exogenous endophthalmitis is a potential complication of intraocular surgery and frequently results in visual impairment. Current treatment involves administration of intravitreal (IVT) antibiotics with or without vitrectomy surgery. Evidence for the use of adjunctive anti-inflammatory agents is conflicting. We set out to determine if bevacizumab, a humanized monoclonal IgG1 antibody targeted against vascular endothelial growth factor (VEGF), has anti-inflammatory properties in experimental models of Gram-positive and Gram-negative inflammation. METHODS: BALB/c mice were subjected to lipopolysaccharide- (LPS) or peptidoglycan- (PGN) induced ocular inflammation and treated with IVT bevacizumab. Iris microvasculature was imaged 6 hours following irritant/treatment using intravital microscopy (IVM) before the mice were euthanized and the eyes were enucleated immediately post-mortem. Following enucleation, levels of VEGF and 23 cytokines and chemokines (IL-1α, IL-1ß, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IL-12 (p40), IL-12 (p70), IL-13, IL-17, TNF, KC, G-CSF, GM-CSF, Eotaxin, INF-γ, MCP-1, MIP-1α, MIP-1ß, RANTES) were quantified using a multiplex assay. RESULTS: Levels of VEGF were significantly increased during the inflammatory response, triggered by either PGN or LPS. Both the adherence of leukocytes to the iris vascular endothelium and the levels of pro-inflammatory cytokines and chemokines were significantly increased following administration of either irritant. Treatment with bevacizumab decreased levels of leukocyte adherence in LPS-treated eyes, however, not in PGN-treated eyes. Conversely, bevacizumab treatment decreased levels of cytokines and chemokines (TNF, IL-6, MCP-1, MIP-1α, MIP-1ß, RANTES, KC) in PGN-treated eyes, however, not in LPS-treated eyes. CONCLUSIONS: Within a 6-hour window bevacizumab had anti-inflammatory actions that were distinct in both Gram-positive (PIU) and Gram-negative (EIU) models, respectively. Given our findings, this would suggest that bevacizumab may have utility as an adjunctive therapy to IVT antibiotics and vitrectomy in the management of exogenous endophthalmitis.

Optimal Treatment of Retinal Vein Occlusion: Canadian Expert Consensus.

BACKGROUND: The availability of new therapeutic approaches, particularly intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapies, has prompted significant changes to the established treatment paradigms for retinal vein occlusion (RVO). Better visual outcomes and significantly lower rates of adverse events have been noted in multiple large randomized clinical trials and have led to a new standard of care for this sight-threatening condition. OBJECTIVE: To develop an expert consensus for the management of RVO and associated complications in the context of recent clinical evidence. METHODS: The development of a Canadian expert consensus for optimal treatment began with a review of clinical evidence, daily practice, and existing treatment guidelines and algorithms. The expert clinicians (11 Canadian retina specialists) met on February 1, 2014, in Toronto to discuss their findings and to propose strategies for consensus. RESULTS: The result of this expert panel is a consensus proposal for Canadian ophthalmologists and retina specialists treating patients presenting with RVO. Treatment algorithms specific to branch and central RVO (BRVO and CRVO) were also developed. CONCLUSIONS: The consensus provides guidelines to aid clinicians in managing RVO and associated complications in their daily practice. In summary, laser remains the therapy of choice when neovascularization secondary to RVO is detected. Adjunctive anti-VEGF could be considered in managing neovascularization secondary to RVO in cases of vitreous hemorrhage. Intravitreal anti-VEGF should be considered for symptomatic visual loss associated with center-involving macular edema on optical coherence tomography. Patients with BRVO and a suboptimal response to anti-VEGF could be treated with grid laser, and those with CRVO and an inadequate response to anti-VEGF may be candidates for intravitreal steroids.

Cardiac issues of noncardiac drugs: the rising story of avastin in age-related macular degeneration.

Emerging safety data, accompanied with recent demographic trends, point to the need for an in-depth review and consideration of potential consequences that might arise from continuing use of bevacizumab (Avastin®) to treat elderly patients presenting with wet age-related macular degeneration (AMD). Although it is expected that lower doses of Avastin used for intravitreal administration and an intact blood-retina barrier would reduce the systemic exposure of the drug, both animal and human studies suggest that this may not be the case. In addition, emerging real-world and clinical trial data continue to point toward compromises in both cardio- and cerebrovascular safety with Avastin. Thus, clinicians are urged to adopt the highest possible standard of care in the treatment of an already fragile AMD population. Furthermore, postmarketing surveillance and pharmacovigilance with intravitreal anti-VEGF inhibitors should remain a priority.

Contemporary management of diabetic retinopathy in Canada: from guidelines to algorithm guidance.

Recent advances in the therapeutic options and approaches for diabetic retinopathy (DR) and diabetic macular edema (DME) have resulted in improved visual outcomes for many patients with diabetes. Yet, they have also created many clinical dilemmas for treating ophthalmologists and retina specialists, including treatment selection, initiation, frequency and duration. With this in mind, a panel of Canadian retina specialists met and discussed the current clinical evidence as well as specific situations and scenarios commonly encountered in daily practice. They also shared their experiences and therapeutic approaches. This document, containing a consensus on treatment algorithms for various clinical scenarios, is the result of their lengthy and in-depth discussions and considerations. The intent is to provide a step-by-step approach to the treatment of DR and DME. Although clinicians are encouraged to use and refer to these algorithms as a guide for various situations, they are not meant to be a replacement for sound clinical judgment.

A fluorescein angiography-based computer-aided algorithm for assessing the retinal vasculature in diabetic retinopathy.

OBJECTIVE: To present a fluorescein angiography (FA)‒based computer algorithm for quantifying retinal blood flow, perfusion, and permeability, in patients with diabetic retinopathy (DR). Secondary objectives were to quantitatively assess treatment efficacy following panretinal photocoagulation (PRP) and define thresholds for pathology based on a new retinovascular function (RVF) score for quantifying disease severity. METHODS: FA images of 65 subjects (58 patients and 7 healthy volunteers) were included. Dye intensity kinetics were derived using pixel-wise linear regression as a measure of retinal blood flow, perfusion, and permeability. Maps corresponding to each measure were then generated for each subject and segmented further using an ETDRS grid. Non-parametric statistical analyses were performed between all ETDRS subfields. For 16 patients, the effect of PRP was measured using the same parameters, and an amalgam of RVF was used to create an RVF index. For ten post-treatment patients, the change in FA-derived data was compared to the macular thickness measured using optical coherence tomography. RESULTS: Compared to healthy controls, patients had significantly lower retinal and regional perfusion and flow, as well as higher retinal permeability (p < 0.05). Moreover, retinal flow was inversely correlated with permeability (R = -0.41; p < 0.0001). PRP significantly reduced retinal permeability (p < 0.05). The earliest marker of DR was reduced retinal blood flow, followed by increased permeability. FA-based RVF index was a more sensitive indicator of treatment efficacy than macular thickness. CONCLUSIONS: Our algorithm can be used to quantify retinovascular function, providing an earlier diagnosis and an objective characterisation of disease state, disease progression, and response to treatment.

Verteporfin plus ranibizumab for choroidal neovascularization in age-related macular degeneration: twelve-month results of the DENALI study.

PURPOSE: To demonstrate noninferiority of ranibizumab in combination with verteporfin photodynamic therapy (PDT) versus ranibizumab monotherapy in patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration (AMD). DESIGN: Prospective, multicenter, double-masked, randomized, phase IIIb clinical trial. PARTICIPANTS: Three hundred twenty-one patients randomized to receive either ranibizumab 0.5 mg monotherapy (n = 112), standard fluence (SF) verteporfin PDT combination therapy (n = 104), or reduced fluence (RF) verteporfin PDT combination therapy (n = 105). METHODS: Ranibizumab was administered monthly in the monotherapy group. In both combination therapy groups, ranibizumab was initiated with 3 consecutive monthly injections, followed by retreatment as needed (pro re nata) with monthly monitoring. All patients were evaluated monthly for 12 months. MAIN OUTCOME MEASURES: Mean change in best-corrected visual acuity (BCVA) from baseline at month 12 and proportion of patients randomized to either combination therapy with a ranibizumab treatment-free interval of 3 months or longer. RESULTS: Two hundred eighty-six patients (89.1%) completed the 12-month study. Mean BCVA change at month 12 was +5.3 and +4.4 letters with verteporfin SF (n = 103) or verteporfin RF (n = 105) plus ranibizumab, respectively, compared with +8.1 letters with ranibizumab monotherapy (n = 110; adjusted 97.5% confidence interval [CI], (-7.90 to infinity); P = 0.0666; and 97.5% CI, (-8.51 to infinity); P = 0.1178; for combination regimens vs. monotherapy, respectively). Noninferiority of either combination regimen to monthly ranibizumab monotherapy was not demonstrated (primary end point). A ranibizumab treatment-free interval of 3 months or longer was achieved in 92.6% and 83.5% of the patients randomized to verteporfin SF or verteporfin RF groups, respectively, with a mean of 5.1 and 5.7 ranibizumab injections, respectively, and patients in the ranibizumab monotherapy arm received 10.5 injections. At month 12, mean central retinal thickness decreased by 151.7 µm and 140.9 µm for the verteporfin SF and RF groups, respectively, and by 172.2 µm with ranibizumab monotherapy. Safety and tolerability of all 3 regimens were similar to and consistent with previous studies in neovascular AMD. The number of ocular serious adverse events was low and occurred largely as single cases. CONCLUSIONS: Ranibizumab monotherapy or combined with verteporfin PDT improved BCVA at month 12; however, noninferiority (7-letter margin) of combination regimens to ranibizumab monotherapy was not demonstrated. Verteporfin RF did not confer clinical benefits over verteporfin SF. All treatments were well tolerated.

Balancing risk in ophthalmic prescribing: assessing the safety of anti-VEGF therapies and the risks associated with unlicensed medicines.

Vascular endothelial growth factor (VEGF) inhibitor medications such as ranibizumab, pegaptanib and bevacizumab are in use for the treatment of neovascular age-related macular degeneration (AMD) and other retinal conditions, although only ranibizumab and pegaptanib are approved for these conditions. In contrast, bevacizumab was developed for the intravenous systemic treatment of colorectal cancer and is not formulated for intravitreal use, but is commonly used off-label in ophthalmology. European Union legislation permits the use of drugs outside the terms of their licence ('off-label') only under certain circumstances, such as during clinical trials, compassionate/named patient use in the absence of a licensed alternative, emergency scenarios (e.g., pandemics) or at the discretion of a treating physician. In such cases, patients should be fully informed regarding their treatment and any potential risks involved. Off-label drug use can be an important tool to provide patients with treatment in cases of unmet medical need. However, the use of an unlicensed medicinal product, when a suitable licensed alternative is available, puts prescribing physicians at risk of liability if safety issues arise. Emerging clinical evidence suggests safety differences exist between ranibizumab and bevacizumab.

Response of Pediatric Choroidal Neovascularization to Anti-Vascular Endothelial Growth Factor.

Choroidal neovascularization (CNV) is a rare condition in children but poses a substantial threat to vision. Anti-vascular endothelial growth factor (anti-VEGF) therapy is commonly used in the pediatric population to treat retinopathy of prematurity. However, the use of anti-VEGF is less common for childhood CNV due to the rarity of CNV in the pediatric population. We report the case of a 10-year-old male presenting with an idiopathic choroidal neovascular membrane. Following a relapse of subretinal fluid after photodynamic therapy, anti-VEGF (bevacizumab) was injected and resulted in remission of the neovascular membrane and improved visual outcome. Further studies are required to elucidate the long-term outcomes associated with the use of anti-VEGF in pediatric patients.

Identifying gaps in patient access to diabetic screening eye examinations in Ontario: a provincially representative cross-sectional study.

OBJECTIVE: Diabetes is the leading cause of acquired blindness in Canadians under the age of 50 years, and diabetic retinopathy affects an estimated 500 000 Canadians. Early identification of retinopathy with screening eye examinations allows for secondary prevention. To understand the need for resource allotment in diabetic screening, we undertook a cross-sectional study of key demographics and geographics of screened and unscreened patients in Ontario. METHODS: Ontario Health Insurance Plan (OHIP) records were derived from physician and optometry billing, matched with patients aged >19 years with prevalent diabetes between 2011 and 2013. Data were cross-correlated with demographic covariates, including age, sex, income quintile, immigrant status, as well as geographic covariates such as rurality and patient Local Health Integration Network (LHIN). RESULTS: Of almost 1 146 000 patients included in the analysis, approximately 406 000 were unscreened. Of note, this included 234 000 adults aged 40-64 years. Approximately 818 000 patients with diabetes lived in large cities, and 301 000 (37%) were unscreened. When the City of Toronto was analyzed as an urban area with the highest density of unscreened prevalence, autocorrelation between the percentage of eye examinations among patients with diabetes aged >40 years and low-income revealed that large areas of Toronto Central correlated for low examination rates and low income. The majority (13/22) of Community Health Centres are present in these areas. CONCLUSIONS: Large cross-sectional population statistics for diabetes prevalence and ophthalmic examinations provides a geographic and socioeconomic profile for populations of middle-aged adults in large urban areas at risk for developing diabetic retinopathy and who might benefit from interventions to improve the rates of screening eye examinations.

Economic burden of bilateral neovascular age-related macular degeneration: multi-country observational study.

BACKGROUND: There is limited previous research examining the healthcare costs of neovascular age-related macular degeneration (NV-AMD), which constrains our understanding of the economic impact of this condition. With aging populations, this leading cause of rapid vision loss in Western countries is expected to become a pressing health predicament, requiring decision makers to evaluate alternative treatment strategies for AMD. OBJECTIVE: To document the economic burden of bilateral NV-AMD, the late stage of AMD, in elderly patients, from a societal perspective. STUDY DESIGN, SETTING AND PARTICIPANTS: A cross-sectional, observational study surveyed 401 patients with bilateral NV-AMD and 471 non-AMD subjects in Canada, France, Germany, Spain and the UK. Physicians' records and subjects' standardized telephone interviews were used to record medical resource utilization, assistance with daily living and social benefits. Annual bilateral NV-AMD-related socioeconomic costs were calculated in euro, year 2005 values. MAIN OUTCOME MEASURES: Societal costs including direct vision-related medical costs (e.g. treatment of AMD and vision-related equipment), direct non-vision-related medical costs (e.g. medications) and direct non-medical-related costs (e.g. home healthcare and social services) were the main outcome measures. RESULTS: The demographic profile of NV-AMD patients was similar across countries; however, co-morbid condition profiles varied. NV-AMD patients reported substantial health-related problems and associated health resource utilization (HRU). In the previous 12 months, 12-22% of patients fell, and half of these patients required medical treatments. More than 20% (range 21-59%) of patients were prescribed vision-enhancing equipment. More than half of the patients (54-81%) were living with a spouse or family member and 19-41% reported receiving assistance for activities of daily living. The average annual societal cost per bilateral NV-AMD patient treated was estimated to be euro 7879 in Canada, euro 7349 in France, euro 12 445 in Germany, euro 5732 in Spain and euro 5300 in the UK, and direct vision-related medical costs accounted for 23-63% of the total cost. Half of the patients were diagnosed with bilateral NV-AMD for <1 year, with an average length of 5 months; there were no statistically significant differences in total annual costs per patient between these patients and those who were diagnosed with bilateral disease for > or =1 year. Estimated annual societal costs of bilateral NV-AMD patients in these countries ranged from euro 268 to euro 1311 million. Estimated annual societal costs of all NV-AMD patients in these countries ranged from euro 671 to euro 3278 million. CONCLUSIONS: Bilateral NV-AMD imposes significant functional impairment on patients, leading to increased HRU and a high societal cost burden. Differences in national healthcare systems and NV-AMD treatment patterns were reflected in the wide variation of NV-AMD costs across the five surveyed countries. Even though the prevalence rates and per-patient costs varied by country, the societal costs of NV-AMD patients were substantial in each country. Earlier intervention with effective therapies is expected to reduce disease burden and disability associated with NV-AMD and, thus, decrease the overall societal cost.

Use of fluorescein and indocyanine green angiography in polypoidal choroidal vasculopathy patients following photodynamic therapy.

BACKGROUND: Exudative age-related macular degeneration (AMD) is a sight-threatening event in many elderly people. Some patients have a much better outcome in visual acuity (VA) than others after treatment with photodynamic therapy (PDT) with verteporfin. The combination of fluorescein angiography (FA) and indocyanine green (ICG) angiography using the Heidelberg Retina Angiograph II (HRA 2) should make a delineation of distinct pattern(s) possible in order to better select and assess therapy. METHODS: This is a retrospective, case-control, single-centre study. We identified a total of 168 eyes of 168 patients from July 2003 to June 2006, including 30 eyes of 30 patients with better visual outcome, defined in this study as VA < or = 0.48 logMAR (> or =20/60 Snellen chart) at the end of the study. Best-corrected VA, maximal central retinal thickness as measured by optical coherence tomography, and results of the FA/ICG angiography using the HRA 2 were analyzed. In this article, we discuss patients with polypoidal choroidal vasculopathy (PCV) and their characteristics. RESULTS: The average follow-up time was 15.3 months (range 4-28 months). Seventeen (57%) of the 30 patients with better visual outcome had PCV. All patients in the group with better visual outcome needed fewer PDT treatments compared with our control group of patients with an exudative AMD. INTERPRETATION: Simultaneous FA/ICG angiography using the HRA 2 allowed delineation of a subgroup of patients with PCV who showed a better visual outcome compared with those with other types of exudative AMD, after treatment with PDT.

Predictors of visual outcomes in patients with neovascular age-related macular degeneration treated with anti-vascular endothelial growth factor therapy: post hoc analysis of the VIEW studies.

PURPOSE: Identify predictors for response to anti-vascular endothelial growth factor (VEGF) therapy in patients with neovascular (wet) age-related macular degeneration (nAMD). METHODS: Retrospective, post hoc analysis of VIEW 1/2. Patients were randomized 1:1:1:1 to 0.5 mg intravitreal aflibercept (IVT-AFL) injection every 4 weeks (0.5q4); 2 mg IVT-AFL every 4 weeks (2q4); 2 mg IVT-AFL every 8 weeks (2q8) after an initial three injections at weeks 0, 4 and 8 or 0.5 mg intravitreal ranibizumab every 4 weeks (0.5q4). RESULTS: 1815 patients [IVT-AFL 2q4 (n = 613); IVT-AFL 2q8 (n = 607); ranibizumab 0.5q4 (n = 595)] were included. Baseline demographics/characteristics were evenly balanced. Younger age (49-69 years), lower visual acuity (VA) [10.0-≤45.0 Early Treatment Diabetic Retinopathy Study (ETDRS) letters] and smaller choroidal neovascularization (CNV) size [0.0-≤3.1 disc areas (DA)] at baseline were associated with the most vision gain (≥15 letters) over 52 weeks (all nominal p < 0.0001).Younger age, higher baseline VA (>64.0-≤83.0 letters) and smaller CNV size were associated with a VA ≥20/40 at week 52. Predominantly classic CNV at baseline (nominal p = 0.0007), older age (≥90 years), lower baseline VA (10.0-≤ 45.0 ETDRS letters) and larger CNV size (>10.1-≤32.6 DA) were all associated with a VA ≤20/200 at week 52 (all nominal p < 0.0001). Along with treatment (nominal p < 0.0001), lower VA (p = 0.0166) and smaller central retinal thickness (both nominal p = 0.0190) were predictors for dry retina development. CONCLUSION: Younger age, lower VA and smaller CNV size at baseline were all associated with greater vision gains over 52 weeks while younger age, higher VA and smaller CNV size at treatment start were more likely to achieve best-corrected VA 20/40 or better after a year's treatment, suggesting the benefit of early anti-VEGF treatment.

Systemic Safety in Ranibizumab-Treated Patients with Neovascular Age-Related Macular Degeneration: A Patient-Level Pooled Analysis.

TOPIC: This study evaluated the cardiovascular/cerebrovascular safety profile of ranibizumab 0.5 mg versus sham ± verteporfin in patients with neovascular age-related macular degeneration (nAMD). In addition, comparisons of ranibizumab 0.3 mg with sham and ranibizumab 0.5 mg to 0.3 mg were performed. CLINICAL RELEVANCE: Intravitreal anti-vascular endothelial growth factor (VEGF) agents carry potential increased systemic risks, including cardiovascular or cerebrovascular events. Pooled safety analyses allow better interpretation of safety outcomes seen in individual clinical trials, especially for less common events. To our knowledge, this is the largest patient-level pooled analysis of patients with nAMD treated with ranibizumab. METHODS: Patient-level pooled analysis of data from 7 Genentech- and Novartis-sponsored phase II, III, and IV studies in nAMD that were completed by December 31, 2013. Pairwise comparisons (primary comparison: ranibizumab 0.5 mg [globally approved dose for nAMD] vs. sham or verteporfin) were performed using Cox proportional hazard regression (hazard ratios [HRs], 95% confidence intervals [CIs]) and rates per 100 patient-years. Standardized Medical Dictionary for Regulatory Activities queries (SMQs) and extended searches were used to identify relevant safety endpoints, including arterial thromboembolic events (ATEs), myocardial infarction (MI), stroke or transient ischemic attack (TIA), stroke (excluding TIA), vascular deaths, and major vascular events as defined by the Antiplatelet Trialists' Collaboration (APTC). RESULTS: The HRs (95% CIs) for the primary comparison of ranibizumab 0.5 mg (n=480) versus sham or verteporfin (n=462) were 1.16 (0.72-1.88) for ATE, 1.33 (0.59-2.97) for MI, 1.43 (0.54-3.77) for stroke excluding TIA, 1.25 (0.61-2.55) for stroke or TIA, 0.57 (0.18-1.78) for vascular death, and 1.12 (0.64-1.98) for APTC events. Hazard ratio 95% CIs included 1, indicating no significant treatment differences, for all endpoints for comparison of ranibizumab 0.5 mg versus sham or verteporfin. CONCLUSIONS: The rates of cardiovascular and cerebrovascular events were low in these patients with nAMD and not clinically meaningfully different for patients treated with ranibizumab 0.5 mg versus sham or verteporfin, which supports the favorable benefit-risk profile of ranibizumab in the patient population with nAMD. Pooling these studies allows an analysis with higher power and precision compared with individual study analyses.

Burden and health care resource utilization in neovascular age-related macular degeneration: findings of a multicountry study.

OBJECTIVE: To describe the burden of bilateral neovascular age-related macular degeneration (NV-AMD) on patient-reported functioning and health resource utilization. METHODS: A cross-sectional study of 401 patients with bilateral NV-AMD and 471 elderly control subjects without AMD was conducted in 5 countries. Subjects completed a telephone survey, including the National Eye Institute 25-Item Visual Function Questionnaire, the EuroQol instrument, the Hospital Anxiety and Depression Scale, and history of falls, fractures, and health care resource utilization. RESULTS: The mean age for patients with NV-AMD was 78.1 years, and 65% were women. The patients reported 45% worse vision-related functioning, 13% worse overall well-being, and 30% more anxiety and 42% more depression symptoms than controls after adjusting for covariates (all, P < .001). The effect of NV-AMD was also observed as a doubled fall rate (16% vs 8% [P < .001]) and a quadrupled need for assistance with daily activities (29% vs 7% [P < .001]) in the patients compared with controls. CONCLUSIONS: The evidence of extensive decline in quality of life and increased need of daily living assistance for patients with NV-AMD compared with a control population substantiates the need for new treatments that prevent vision loss and progression to blindness.

Burden of illness of neovascular age-related macular degeneration in Canada.

BACKGROUND: Age-related macular degeneration (AMD) is a retinal disease affecting more than 2 million Canadians over the age of 50. The neovascular form of AMD is responsible for 90% of severe vision loss associated with the disease. This study was conducted to assess the burden of neovascular AMD in the Canadian population. METHODS: A cross-sectional, observational study was conducted of self-reported functional health, well-being, and disease burden among elderly subjects in Canada with (n = 67) and without (n = 99) neovascular AMD. Subjects completed telephone surveys of the National Eye Institute Visual Function Questionnaire (NEI-VFQ-25), the EuroQol questionnaire (EQ-5D), and the Hospital Anxiety and Depression Scale (HADS). Subjects also reported their history of falls and fractures and annual health care resource utilization. RESULTS: Subjects with neovascular AMD reported significantly worse vision-related functioning and overall well-being than controls (adjusted mean scores on the NEI-VFQ-25: 48.0 vs. 87.5; p < 0.0001) and significantly more depression symptoms than controls (HADS depression: 5.8 vs. 4.3; p = 0.037). Subjects with neovascular AMD also reported more than twice the need for assistance with daily activities compared with controls (19.4% vs. 9.1%; p = 0.013) and a nearly 3 times higher fall rate than the control group (22.4% vs. 8.1%; p = 0.014). The annual neovascular AMD cost per patient was Can dollars 11,334, which is over 8 times that of elderly subjects without neovascular AMD (Can dollars 1,412). Over half of the neovascular AMD costs were direct medical costs. INTERPRETATION: Neovascular AMD is associated with significant limitation in functional abilities and quality of life, resulting in increased health care resource utilization and high patient support costs. These findings emphasize the need for new treatments for neovascular AMD that will prevent vision loss and progression to blindness in order to lessen the ensuing economic burden.

Ranibizumab in Diabetic Macular Oedema - A Benefit-risk Analysis of Ranibizumab 0.5 mg PRN Versus Laser Treatment.

INTRODUCTION: The structured Benefit-risk Action Team (BRAT) approach aims to assist healthcare decision makers in treatment assessments. We applied BRAT to compare the benefit-risk profile of ranibizumab 0.5 mg versus laser photocoagulation for the treatment of diabetic macular oedema (DMO). METHODS: One-year data for the ranibizumab 0.5 mg pro re nata (PRN) and laser arms of the phase III trials RESPOND (NCT01135914; n=220), RESTORE (NCT00687804; n=345), and REVEAL (NCT00989989; n=396) were included in the analysis. The benefit measures included ≥10 letters gain/avoidance of loss in best-corrected visual acuity (BCVA), achieving central retinal thickness (CRT) <275 µm, and 25-item Visual Function Questionnaire (VFQ-25) outcomes. The risks measures included endophthalmitis, intraocular pressure increase, hypertension, proteinuria, arterial/venous thromboembolic events and deaths. RESULTS: Ranibizumab treatment provided significant benefits compared with laser for ≥10 letter BCVA gain at month 12 (387/1,000 versus 152/1,000 patients), CRT <275 µm at 12 months (474/1,000 versus 348/1,000 patients), and improvement of ≥6.06 on the VFQ-25 near activities subscale (325/1,000 versus 245/1,000 patients). Results for the risk measures were similar for both treatments. CONCLUSIONS: Superior clinically relevant outcomes were observed with ranibizumab 0.5 mg PRN compared with laser without compromising on safety. This analysis further supports the positive benefit-risk profile of ranibizumab 0.5 mg PRN.

VEGF-A is increased in exogenous endophthalmitis.

OBJECTIVE: Exogenous endophthalmitis is an ophthalmologic emergency defined by panocular inflammation. Vascular endothelial growth factor A (VEGF-A) contributes to inflammation by promoting chemotaxis of monocytes and granulocytes and by increasing vascular permeability. The purpose of this article is to determine if VEGF-A is elevated in the vitreous samples obtained from individuals with exogenous endophthalmitis. METHODS: Vitreous samples from individuals with exogenous endophthalmitis (n = 18) were analyzed via Luminex assay and enzyme-linked immunosorbent assay for the cytokines VEGF-A, tumor necrosis factor (TNF), interleukin 6 (IL-6), IL-8 (chemokine [CXCL]-8), IL-1ß, IL-10, IL-12p70, IL-33, interferon (IFN)-γ, IFN-α, IFN-ß, chemokine ligand (CCL)-3, IL-2, IL-5, IL-15, CXCL-10, CCL-2, IL-1Ra, CCL-5, IL-17, and CCL-11. Vitreous samples obtained at the time of macular hole surgery served as controls (n = 8). RESULTS: Concentrations of VEGF-A were significantly elevated in vitreous samples from individuals with exogenous endophthalmitis compared with macular hole (p < 0.001). VEGF-A was significantly upregulated in individuals with exogenous endophthalmitis after cataract surgery (p = 0.001), vitrectomy (p = 0.024), and intravitreal injection (p = 0.012). VEGF-A concentrations were similar in both culture-positive and culture-negative populations (p > 0.05). In a linear regression model, levels of VEGF-A correlated significantly with the chemokine CXCL-8 (p = 0.028). CONCLUSIONS: We demonstrate that VEGF-A is potently upregulated in exogenous endophthalmitis. This observation provides a foundation for future studies of targeted VEGF-A blockade in the management of endophthalmitis.

The letter contrast sensitivity test: clinical evaluation of a new design.

PURPOSE: To compare the reliability, validity, and responsiveness of the Mars Letter Contrast Sensitivity (CS) Test to the Pelli-Robson CS Chart. METHODS: One eye of 47 normal control subjects, 27 patients with open-angle glaucoma, and 17 with age-related macular degeneration (AMD) was tested twice with the Mars test and twice with the Pelli-Robson test, in random order on separate days. In addition, 17 patients undergoing cataract surgery were tested, once before and once after surgery. RESULTS: The mean Mars CS was 1.62 log CS (0.06 SD) for normal subjects aged 22 to 77 years, with significantly lower values in patients with glaucoma or AMD (P<0.001). Mars test-retest 95% limits of agreement (LOA) were +/-0.13, +/-0.19, and +/-0.24 log CS for normal, glaucoma, and AMD, respectively. In comparison, Pelli-Robson test-retest 95% LOA were +/-0.18, +/-0.19, and +/-0.33 log CS. The Spearman correlation between the Mars and Pelli-Robson tests was 0.83 (P<0.001). However, systematic differences were observed, particularly at the upper-normal end of the range, where Mars CS was lower than Pelli-Robson CS. After cataract surgery, Mars and Pelli-Robson effect size statistics were 0.92 and 0.88, respectively. CONCLUSIONS: The results indicate the Mars test has test-retest reliability equal to or better than the Pelli-Robson test and comparable responsiveness. The strong correlation between the tests provides evidence the Mars test is valid. However, systematic differences indicate normative values are likely to be different for each test. The Mars Letter CS Test is a useful and practical alternative to the Pelli-Robson CS Chart.

Choroidal neovascularization with interferon associated retinopathy: case report and review of literature.

We report a case of new interferon-associated ocular complication during treatment with combination of pegylated interferon plus ribavirin for chronic hepatitis C infection. Our patient developed choroidal neovascularization in addition to the classic interferon associated retinopathy. Choroidal neovascularization has not been reported before in association with interferon induced retinopathy. We describe our management to control the ocular symptoms and the retinal lesions with one year follow up. We also provide literature report on the natural history, the pathophysiology and the variable characteristics of interferon associated retinopathy versus hepatitis C related ophthalmopathy.