Photodynamic Therapy With Verteporfin Research Articles

Impact of methylenetetrahydrofolate reductase C677T polymorphism on the efficacy of photodynamic therapy in patients with neovascular age-related macular degeneration

The most severe visual impairments due to age-related macular degeneration (AMD) are frequently caused by the occurrence of choroidal neovascularization (CNV). Although photodynamic therapy with verteporfin (PDT-V) is currently a second-line treatment for neovascular AMD, it can be conveniently combined with drugs acting against vascular endothelial growth factor (anti-VEGF) to reduce the healthcare burden associated with the growing necessity of anti-VEGF intravitreal re-injection. Because the common 677 C > T polymorphism of the methylenetetrahydrofolate reductase gene (MTHFR-C677T; rs1801133) has been described as predictor of satisfactory short-term responsiveness of AMD-related CNV to PDT-V, we retrospectively examined the outcomes of 371 Caucasian patients treated with standardized, pro-re-nata, photodynamic regimen for 24 months. Responder (R) and non-responder (NR) patients were distinguished on the basis of the total number of scheduled PDT-V (TN-PDT-V) and change of best-corrected visual acuity (∆-BCVA). The risk for both TN-PDT-V and ∆-BCVA to pass from R to NR group was strongly correlated with CT and TT genotypes of MTHFR-C677T variant resulting, respectively, in odd ratios of 0.19 [95% CI, 0.12–0.32] and 0.09 [95% CI, 0.04–0.21] (P < 0.001), and odd ratios of 0.24 [95% CI, 0.15–0.39] and 0.03 [95% CI, 0.01–0.11] (P < 0.001). These pharmacogenetic findings indicate a rational basis to optimize the future clinical application of PDT-V during the combined treatments of AMD-related CNV, highlighting the role of thrombophilia to be aware of the efficacy profile of photodynamic therapy.

Effect of Factor XIII-A G185T Polymorphism on Visual Prognosis after Photodynamic Therapy for Neovascular Macular Degeneration.

Macular degenerations represent leading causes of central blindness or low vision in developed countries. Most of these severe visual disabilities are due to age-related macular degeneration (AMD) and pathologic myopia (PM), both of which are frequently complicated by subfoveal choroidal neovascularization (CNV). Photodynamic therapy with verteporfin (PDT-V) is still employed for CNV treatment in selected cases or in combined regimen. In Caucasian patients, the common polymorphism G185T of factor XIII-A gene (FXIII-A-G185T; rs5985) has been described as predictor of poor angiographic CNV responsiveness to PDT-V. Nevertheless, the prognostic implications of this pharmacogenetic determinant on long-term visual outcome after a PDT-V regimen have not been evaluated. We retrospectively selected Caucasian patients presenting with treatment-naive CNV and receiving standardized PDT-V protocol for two years. The study population included patients affected by subfoveal CNV secondary to AMD or PM. We assessed the correlations between the polymorphic allele T of FXIII-A-G185T and: (1) total number of photodynamic treatments; and (2) change in visual acuity from baseline to the end of the follow-up period. Considering a total study population of 412 patients with neovascular AMD or PM, the carriers of 185 T-allele of FXIII-A (GT or TT genotype) received a higher number of photodynamic treatments than patients without it (GG wild-type genotype) (p < 0.01; mean number of PDT-V: 5.51 vs. 3.76, respectively). Moreover, patients with 185 T-allele of FXIII-A had a more marked worsening of visual acuity at 24 months than those with the GG-185 wild genotype (p < 0.01; mean difference in logMAR visual acuity: 0.22 vs. 0.08, respectively). The present findings show that the G185T polymorphism of the FXIII-A gene is associated with significant differences in the long-term therapeutic outcomes of patients treated with standardized PDT-V protocol. The comprehensive appraisal of both anti-thrombophilic effects due to FXIII-A G185T variant and photo-thrombotic action of PDT-V toward CNV provides several clues about the rationale of this intriguing pharmacogenetic correlation. Further investigations are warranted to outline the appropriate paradigm for guiding PDT-V utilization in the course of the combined therapeutic protocol for neovascular macular degeneration.

Photodynamic therapy for diffuse choroidal hemangioma in sturge-weber syndrome.

Purpose. To report the treatment outcome of photodynamic therapy with verteporfin (PDT) for exudative retinal detachment (RD) associated with diffuse choroidal hemangioma in Sturge-Weber syndrome (SWS). Methods. An interventional case report of a 10-year-old girl with SWS who developed an exudative RD (visual acuity hand motions) that was treated with PDT. She was treated with a first session of multispot PDT. Posteriorly, a choroidotomy for drainage of subretinal fluid was created, combined with an intravitreal injection of gas (SF6) and cryoapplication. Finally, a second session of PDT was applied. Results. Subretinal fluid resolved over a period of one year and visual acuity increased to 20/125. Conclusions. PDT is an effective therapeutic option for exudative RD associated with diffuse choroidal hemangioma.

Genetic Predictors of Response to Photodynamic Therapy

In Western countries, therapeutic management of patients affected by choroidal neovascularization (CNV) secondary to different typologies of macular degeneration represents a major health care problem. Age-related macular degeneration is the disease most frequently associated with CNV development. Schematically, CNVs can be distinguished into classic and occult subtypes, which are characterized by variable natural history and different responsiveness to some therapeutic procedures. At present, the dramatic vision loss due to CNV can be mainly treated by two interventional strategies, which are utilizable in either single or combined modalities: photodynamic therapy with verteporfin (PDT-V), and intravitreal administration of drugs acting against vascular endothelial growth factor. The combined use of PDT-V and anti-angiogenic drugs represents one of the most promising strategies against neovascular macular degeneration, but it unavoidably results in an expensive increase in health resource utilization. However, the positive data from several studies serve as a basis for reconsidering the role of PDT-V, which has undergone a renaissance prompted by the need for a more rational therapeutic approach toward CNV. New pharmacogenetic knowledge of PDT-V points to exploratory prospects to optimize the clinical application of this intriguing photothrombotic procedure. In fact, a Medline search provides data regarding the role of several single nucleotide polymorphisms (SNPs) as genetic predictors of CNV responsiveness to PDT-V. Specifically, correlations between SNPs and different levels of PDT-V efficacy have been detected by examining the gene variants influencing (i) thrombo-coagulative pathways, i.e. methylenetetrahydrofolate reductase (MTHFR) 677C>T (rs1801133), factor V (F5) 1691G>A (rs6025), prothrombin (F2) 20210G>A (rs1799963), and factor XIII-A (F13A1) 185G>T (rs5985); (ii) complement activation and/or inflammatory processes, i.e. complement factor H (CFH) 1277T>C (rs1061170), high-temperature requirement factor A1 (HTRA1) promoter -512G>A (rs11200638), and two variants of the C-reactive protein (CRP) gene (rs2808635 and rs876538); and (iii) production and bioavailability of vascular endothelial growth factor (VEGFA -2578C>A [rs699947] and rs2146323). This article critically evaluates both the clinical plausibility and the opportunity to utilize the most important SNP-response interactions of PDT-V for an effective upgrade of the current anti-CNV therapeutic scenario. In addition, the pharmacogenetics of a very severe post-PDT-V adverse event, i.e. a decrease in acute vision, is briefly discussed. A comprehensive appraisal of the findings reviewed in this article should be carefully considered to design future trials aimed at verifying (after proper genotypic stratification of the enrolled patients) whether these innovative pharmacogenetic approaches will be able to improve the multifaceted interventional management of neovascular macular degeneration.

Single-session combined photodynamic therapy with verteporfin and intravitreal anti-vascular endothelial growth factor therapy for chronic central serous chorioretinopathy: a pilot study at 12-month follow-up

To report the anatomic and functional outcomes of a single-session combined photodynamic therapy with verteporfin (PDT) and intravitreal (IVT) anti-vascular endothelial growth factor (anti-VEGF) in patients with chronic central serous chorioretinopathy (CCSCR). Retrospective interventional comparative case series of eyes with symptomatic CCSCR (duration ≥ 4 months) and macular neurosensory retinal detachment (MNSRD). The study group, eight eyes (six patients), received a single session of combined full-fluence PDT and IVT anti-VEGF [bevacizumab (2.5 mg), four eyes; pegaptanib sodium [0.3 mg], four eyes). A matched control group, ten eyes (seven patients), treated with full-fluence PDT alone, was included. All patients had 12 months of follow-up. The mean CCSCR duration was 12.5 ± 14.2 months (range: 4-47 months) in the study group. In the control group, the mean CCSCR duration was 15.3 ± 7.5 months (range: 4-24 months). In the study group, the mean logarithm of the minimum angle of resolution (logMAR) best-corrected visual acuity (BCVA) improved from 0.6 (20/80) to 0.2 (20/30) (P = 0.011). Central macular thickness (CMT) measured by optical coherence tomography (OCT) decreased from 288.4 μ (range: 165-375 μ) at baseline to a CMT of 163.1 μ (range: 120-200 μ) (P = 0.005) at 12 months. In the control group, the mean logMAR BCVA improved from 0.7 (20/100) to 0.6 (20/80) (P = 0.43). CMT decreased from 332.9 μ (range: 171-495 μ) at baseline to a CMT of 213.1 μ (range: 133-307 μ) (P = 0.002) at 12 months. At 12 months, MNSRD resolved completely in eight eyes (100%) and in seven eyes (70%), in the study group and the control group respectively. In the control group, four eyes (40%) required more than one PDT session (mean: 2.6 sessions; range: 2-4) due to persistent MNSRD. Retinal pigment epithelium (RPE) atrophy changes but no leakage were seen by fluorescein angiography in all eight eyes (100%) in the study group, and in three out of ten eyes (30%) in the control group. No systemic adverse events were observed. Combined PDT and IVT anti-VEGF therapy seems to aid in the resolution of MNSRD in patients with CCSCR. Combination therapy was associated with a rapid reduction in MNSRD and improvement in BCVA with no recurrences at 12 months. However, combination therapy with full-fluence PDT has the potential to accelerate RPE atrophy, and this needs further study.

Pharmacogenetic Aspects in Therapeutic Management of Subfoveal Choroidal Neovascularisation: Role of Factor XIII-A 185 T-Allele

In Western Countries, the occurrence of choroidal neovascularization (CNV) secondary to different forms of macular degeneration represents a common cause of blindness. Particularly, age-related macular degeneration (AMD) and pathologic myopia (PM) are the most frequent diseases related to CNV development. At present, the combined employment of drugs acting against vascular endothelial growth factor (anti-VEGF) and photodynamic therapy with verteporfin (PDT-V) is a promising therapeutic strategy for neovascular macular degenerations. However, this approach inevitably leads to an increase in health-resource utilization. In several clusters of patients treated for CNV, correlations among common gene polymorphisms implicated in coagulation- or complement-cascade and different levels of, respectively, post-PDT-V or post-anti-VEGF benefit have been reported. Factor XIII-A G185T substitution (rs5985), a frequent anti-thrombophilic genetic variant of Caucasian ethnic groups, unequivocally influences a worsening of the CNV responsiveness to PDT-V in patients affected by either AMD- or PM-related CNV. These coherent pharmacogenetic findings point out the opportunities to: i. optimize the eligibility criteria of PDT-V and, ii. customize the interventional strategy against CNV, for finally minimizing the socio-economic burden of neovascular macular degenerations.

Central serous chorioretinopathy: a pathogenetic model

Despite numerous studies describing predominantly its demography and clinical course, many aspects of central serous chorioretinopathy (CSCR) remain unclear. Perhaps the major impediment to finding an effective therapy is the difficulty of performing studies with large enough cohorts, which has meant that clinicians have focused more on therapy than on a deeper understanding of the pathogenesis of the disease. Hypotheses on the pathogenesis of CSCR have ranged from a basic alteration in the choroid to an involvement of the retinal pigment epithelium (RPE). Starting from evidence that affected subjects often present a personality prone to stress with altered pituitary–hypothalamic axis response (HPA) and that they have higher levels of serum and urinary cortisol and catecholamines than healthy subjects, we hypothesize a cascade of events that may lead to CSCR through hypercoagulability and augmented platelet aggregation. In particular we investigated the role of tissue plasminogen activator, increasing plasminogen activator inhibitor 1 (PAI-1), and plasmin-α2- plasmin inhibitor complexes. We reviewed the different therapeutic approaches, including adrenergic antagonists, carbonic anhydrase inhibitors, mifepristone, ketoconazole, laser photocoagulation, intravitreal injection of bevacizumab, and photodynamic therapy with verteporfin (PDT) and our model of pathogenesis seems to be in agreement with the clinical effects obtained from these treatments. In accord with our thesis, we began to treat a group of patients affected by CSCR with low-dose aspirin (75–100 mg), because of its effectiveness in other vascular diseases and its low ocular and general toxicity with prolonged use. The formulation of a causative model of CSCR enables us to understand how the therapeutic approach cannot be based on a generalized therapy but should be individualized for each patient, and that sometimes a combined strategy of treatment is required. Moreover a complete knowledge of the disease will help to identify patients prone to the most persistent forms of CSCR, and thus help to find a treatment.

Combined intravitreal ranibizumab and verteporfin photodynamic therapy versus ranibizumab alone for the treatment of age-related macular degeneration

To compare same-day combined therapy of photodynamic therapy with verteporfin (PDT-V) and intravitreal ranibizumab versus monotherapy with ranibizumab for the treatment of choroidal neovascularization. IN THIS PROSPECTIVE STUDY, THE TOTAL NUMBER OF EYES WAS RANDOMIZED INTO TWO GROUPS: in the first, treatment consisted of a combined therapy of PDT-V and ranibizumab 0.5 mg on the same day; in the second, ranibizumab 0.5 mg in 3 monthly injections. Best-corrected visual acuity (BCVA) and central macular thickness (CMT) on optical coherence tomography (OCT) were recorded before and 6 months after treatment. A total of 47 eyes of 47 subjects were enrolled in the study. In the combined-therapy group (group 1), the mean baseline BCVA ± standard deviation (SD) was 32.65 ± 11.09 letters (Snellen equivalent, 20/59); in the ranibizumab-alone group (group 2), 29.13 ± 9.03 letters (20/70). At 6 months' follow-up, in group 1 the mean baseline BCVA was 39.06 ± 10.12 letters (20/42); in group 2, 33.87 ± 12.06 letters (20/57). Improvement was significant in both group 1 (P = 0.03) and group 2 (P = 0.002). In group 1, the mean CMT at baseline ± SD was 315 ± 95.49 μm; in group 2, 306.33 ± 71.61 μm. At 6 months' follow-up, in group 1 it was 202 ± 52.02 μm; in group 2, 226 ± 65.58 μm. Reduction was significant in both group 1 (P = 0.0007) and group 2 (P = 0.00001). After 6-months, the rate of retreated eyes was 29.4% in group 1 and 43.3% in group 2. The need for retreatment did not depend on the treatment protocol (P = 0.34). From a functional and anatomic point of view, the two treatments showed equivalent efficacy, with fewer retreatments in group 1. No serious adverse events, such as retinal detachment, endophthalmitis, or ocular hypertension occurred in either group.

Treatment of Choroidal Neovascularization in High Myopia

High myopia affects approximately 2% of general population, and is a major cause of legal blindness in many developed countries. Choroidal neovascularization (CNV) is the most common vision-threatening complication of high myopia. Different therapeutic approaches have been attempted such as thermal laser photocoagulation, surgery and photodynamic therapy with verteporfin (PDT). The visual outcome of these therapies has been reported to be better than the natural history of the condition. However, the limited visual acuity improvement after PDT monotherapy and the appearance of subretinal fibrosis and chorioretinal atrophy prompted the association of other therapies. In the past few years a tremendous advance in the knowledge of the mechanisms underling CNV secondary to high myopia and age related macular degeneration has been achieved, leading to new therapeutic targets and novel drugs and combined therapies. These new therapeutic weapons have been designed to achieve a selective shut down of choroidal new vessels. Recent reviews have been published on the natural history and therapies for myopic CNV. Ohno-Matsui reported on the natural history of the condition as well as the outcome of laser photocoagulation, surgical extraction of CNV, foveal translocation and photodynamic therapy on myopic CNV in the short-term. Soubrane et al reviewed the new advances on surgery, laser photocoagulation and PDT, considering some of the potential effects of triamcinolone, pegaptanib and ranibizumab in CNV secondary to age related macular degeneration (AMD). Novack et al reported on the pharmacological therapy of CNV in AMD. The aim of this review is to summarize the recent advances in myopic CNV pathophysiology and the new therapeutic targets and drugs that are changing the clinical management of myopic CNV.

Impact of Coagulation-Balance Gene Predictors on Efficacy of Photodynamic Therapy for Choroidal Neovascularization in Pathologic Myopia

To investigate whether different coagulation-balance genetic backgrounds might explain the variable clinical outcomes detected, after a single photodynamic therapy with verteporfin (PDT-V), in Caucasian patients with subfoveal choroidal neovascularization (CNV) secondary to pathologic myopia (PM). Retrospective, consecutive, nonrandomized, interventional cases series. Two hundred thirty-four patients exclusively treated with standardized PDT-V for the presence of PM-related classic CNV. The enrolled patients were subdivided as responders or nonresponders based on CNV responsiveness to the first PDT-V over a 3-month period. Three common gene polymorphisms, factor XIII-A G185T, methylenetetrahydrofolate reductase C677T, and methionine synthase reductase A66G, were genotyped by polymerase chain reaction in each patient. The measures of CNV responsiveness to PDT-V were the changes, respect to baseline, of fluorescein angiography CNV leakage, greatest linear dimension, and area of the lesion. Logistic regression analyses were performed to explore the predictive role of phenotypic (patient's age, baseline visual acuity, and baseline CNV area) and genotypic (all the mentioned mutations) variables regarding PDT-V efficacy. Responders to PDT-V were overrepresented within carriers of methylenetetrahydrofolate reductase 677 T-allele (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.8-5.4; P = 0.001) and, to a minor extent, among patients with better visual acuity at baseline (OR, 11.8; 95% CI, 1.6-88.0; P = 0.02). However, predictors of PDT-V lack of efficacy were patient's age (OR, 0.73; 95% CI, 0.62-0.86; P = 0.01) and, especially, factor XIII-A 185 GT/TT genotypes (OR, 0.19; 95% CI, 0.11-0.35; P = 0.0001). All the other considered predictive factors did not significantly influence the CNV responsiveness to PDT-V. These findings document the presence of pharmacogenetic correlations between common coagulation-balance gene polymorphisms and different CNV responsiveness to PDT-V in Caucasian patients with neovascular PM.

Predictive Role of Gene Polymorphisms Affecting Thrombin-Generation Pathway in Variable Efficacy of Photodynamic Therapy for Neovascular Age-Related Macular Degeneration

Age-related macular degeneration (AMD) represents the leading cause of central blindness in developed countries. The majority of severe vision loss occurs in the neovascular form of AMD, generally characterized by the presence of choroidal neovascularization (CNV) beneath the fovea. Photodynamic therapy with verteporfin (PDT-V) and drugs acting against vascular endothelial growth factor are the most commonly employed treatments for AMD-related subfoveal CNV. The combined use of both these strategies is the most promising therapeutic approach towards this harmful disease. The therapeutic action of PDT-V depends to a photochemical perturbation of thrombo-coagulative processes within CNV. Predictive correlations between peculiar coagulation-balance gene polymorphisms and different levels of post-PDT-V benefit have been recently documented in Caucasian patients with neovascular AMD. Particularly, heterozygous A-allele carriers of factor V Leiden 1691 or prothrombin 20210 gene are characterized by a greater possibility to exhibit clinical benefit after PDT-V. Both mutations induce thrombophilia increasing the thrombin generation in plasma and, thus, they can consistently intensify the photothrombotic phase of the therapeutic CNV occlusion. In prospect, considering the different individual susceptibility to PDT-V, a preoperative assessment of the genotypic thrombophilic background could optimize the eligibility criteria of this intriguing treatment. This review summarizes some of the recent published patents on treatment of neovascular AMD, with a particular attention to PDT-V application in combined therapeutic modalities.

Predictive Role of C677T MTHFR Polymorphism in Variable Efficacy of Photodynamic Therapy for Neovascular Age-Related Macular Degeneration

Age-related macular degeneration (AMD) complicated by subfoveal choroidal neovascularization (CNV) is the leading cause of severe central blindness in developed countries. AMD-related CNVs are distinguishable in classic and occult subtypes, characterized by variable natural history and different responsiveness to therapeutic procedures. Combined and repeated use of photodynamic therapy with verteporfin (PDT-V) and antiangiogenic drugs represents the most promising strategy against neovascular AMD, but it is unavoidably associated with mounting health-resource utilization. Predictive correlations between peculiar coagulation-balance gene variants and different levels of post-PDT-V benefit have recently been documented in Caucasians with AMD-related CNVs. In particular, methylenetetrahydrofolate reductase C677T substitution, a common thrombophilic folate pathway genotypic polymorphism, influences a better CNV responsiveness to PDT-V in classic- but not in occult-CNV cases. These pharmacogenetic findings indicate the opportunities to optimize the eligibility criteria of PDT-V and/or to perform this intriguing therapy in a customized manner, for finally minimizing the socio-economic burden of neovascular AMD.

Coagulation Gene Predictors of Photodynamic Therapy for Occult Choroidal Neovascularization in Age-Related Macular Degeneration

To determine whether different coagulation-balance genetic polymorphisms explain the variable clinical outcomes of photodynamic therapy with verteporfin (PDT-V) in Caucasian patients with occult subfoveal choroidal neovascularization (CNV) due to age-related macular degeneration (AMD). The clinical records of consecutive patients with AMD-related occult CNV, treated with PDT-V for evidence of disease progression, were retrospectively examined. Eighty-four eligible subjects were subdivided into responders and nonresponders based on CNV responsiveness to the first PDT-V over a 3-month period. Six gene polymorphisms (i.e., factor V G1691A, prothrombin G20210A, factor XIII-A G185T, methylenetetrahydrofolate reductase C677T, methionine synthase A2756G, and methionine synthase reductase A66G) were genotyped in each patient. Logistic regression analyses were performed to explore the predictive role of phenotypic and genotypic variables for PDT-V effectiveness. Regression models documented that PDT-V nonresponders were more frequently patients with the hyperfibrinolytic G185T mutation of factor XIII-A (odds ratio [OR], 0.28; 95% confidence interval [CI], 0.11-0.73; P < 0.01). Univariate logistic regression was indicative of an overrepresentation of PDT-V responders among the combined carriers of thrombophilic factor V 1691A and prothrombin 20210A alleles (OR = 3.8; 95% CI: 0.94-15.6; P = 0.07). All the other predictors considered did not significantly influence the short-term CNV responsiveness to PDT-V. These data provide evidence of the presence of a pharmacogenetic relationship between peculiar coagulation-balance genetic backgrounds and different levels of PDT-V effectiveness in patients with AMD with occult CNV.

12-MONTH RETROSPECTIVE STUDY AND REVIEW OF PHOTODYNAMIC THERAPY WITH VERTEPORFIN FOR SUBFOVEAL CHOROIDAL NEOVASCULARIZATION IN AGE-RELATED MACULAR DEGENERATION

To evaluate the 12-month visual outcome of photodynamic therapy with verteporfin (PDT-V) for patients with subfoveal choroidal neovascularization (CNV) secondary to age-related macular degeneration and to verify the predictive role of visual and angiographic factors. This retrospective, interventional, consecutive case series study included subjects with different forms of subfoveal CNV. All patients received PDT-V according to Treatment of Age-Related Macular Degeneration With Photodynamic Therapy/Visudyne in Photodynamic Therapy guidelines. A review of medical and angiographic records was performed. Two hundred sixteen patients were divided into 4 study groups: group I, 60 eyes with classic CNV; group II, 56 eyes with predominantly classic CNV; group III, 42 eyes with minimally classic CNV; and group IV, 58 eyes with occult CNV. In groups I and II, best-corrected visual acuity (BCVA) was moderately decreased, without reaching a statistically noticeable level during the entire follow-up; lesion size reduction only reached significance in group I. Groups III and IV showed evident worsening of BCVA (P < 0.05), despite concomitant reduction in CNV size (statistically remarkable only for occult CNV). All study groups exhibited a significant correlation between higher baseline BCVA and better final visual outcome. In groups II and IV, smaller baseline CNV sizes also favorably influenced final BCVA. Standardized PDT-V minimizes deterioration of central vision only in patients with classic and predominantly classic CNV. Irrespective of the CNV type, better BCVA at presentation represents a good predictive sign. In predominantly classic and occult lesions, minor initial CNV dimension is also a positive prognostic element.

Predictive role of coagulation-balance gene polymorphisms in the efficacy of photodynamic therapy with verteporfin for classic choroidal neovascularization secondary to age-related macular degeneration

Age-related macular degeneration (AMD) represents the leading cause of blindness in Western populations. The majority of severe vision loss occurs in the exudative form of AMD, characterized by the development of choroidal neovascularization (CNV) beneath the fovea. Photodynamic therapy with verteporfin (PDT-V) represents one of the most largely employed modality that maybe achieves the subfoveal CNV inactivation in AMD patients. Although several ocular factors have been hitherto investigated as predictors, these researches have weakly contributed to PDT-V optimization. As PDT-V benefit is determined by CNV photothrombosis, we have retrospectively studied several coagulation-balance gene polymorphisms as predictors of PDT-V efficacy. Ninety Caucasian patients with neovascular AMD were subdivided in responder and nonresponder, on the basis of CNV responsiveness to PDT-V application. Six gene polymorphisms, that is factor V G1691A, prothrombin G20210A, factor XIII-A G185T, methylenetetrahydrofolate reductase C677T, methionine synthase A2756G, and methionine synthase reductase A66G, were genotyped in the entire cohort. Logistic regression models showed that PDT-V responders were more prevalent within patients with prothrombin G20210A mutation [odds ratio (OR)=5.6, 95% confidence interval (CI) (1.2, 27.2), P=0.03], and within methylenetetrahydrofolate reductase 677T carriers [OR=6.9, 95% CI (2.7, 18.1), P<0.001]. Conversely, PDT-V nonresponders were overrepresented in carriers for factor XIII-A 185T [OR=0.13, 95% CI (0.05, 0.36), P<0.001]. These results provide evidences for the presence of pharmacogenetic relationship between peculiar coagulation-balance gene polymorphisms and different levels of PDT-V effectiveness in patients with AMD-related CNV.

Coût-efficacité du traitement par thérapie photodynamique à la verteporfine des membranes néovasculaires dans la dégénérescence maculaire liée à l’âge en pratique clinique en Suisse

Age-related macular degeneration is the leading cause of legal blindness in older people. Choroidal neovascularization (CNV) is treatable with photodynamic therapy with verteporfin (PDT) but is expensive. The aim of this study was to assess the cost-effectiveness of PDT in routine clinical practice in Switzerland. A Markov model was used to analyze the costs of PDT in routine clinical practice. It described patients moving between good or impaired vision (visual acuity [VA]>0.1) and highly impaired vision (VA<0.1). Costs for PDT were based on the results of the Donati open-labeled prospective clinical study. Costs for medical and social management of AMD patients were defined according to Grainer's study. The cost of PDT varied from 8,800 to 10,969 euros/patient/year. Ninety percent of the patients retained a VA > or =0.1. Health costs saved by keeping patients from moving to the highly impaired vision group was 4,248 euros/patient/year. Incremental costs per vision-year saved varied from 8,239 to 10,271 euros. Cost per quality-adjusted life year (QALY) gained at 5 years was 65,150 euros. PDT was found to be moderately cost-effective in Switzerland. The longer the follow-up, the more cost-effective Visudyne was. Cost-effectiveness is a country-dependent assessment and analyses should be done for each health care system. PDT was found to be cost-effective in Switzerland (category C of Laupaci's classification).

Effect of posterior juxtascleral triamcinolone acetonide on the efficacy and choriocapillaris hypoperfusion of photodynamic therapy

To evaluate the effect of posterior juxtascleral triamcinolone acetonide (TA) injection combined with photodynamic therapy with verteporfin (PDT) for treating exudative age-related macular degeneration (AMD), the best-corrected visual acuity (BCVA), the retreatment rates and the rate of choroidal hypoperfusion were investigated. A total of 67 eyes with subfoveal choroidal neovascularization (CNV) due to AMD were included. Forty-four eyes underwent PDT alone (PDT-alone group), and 23 eyes underwent PDT with the posterior juxtascleral injection of TA (PDT+TA group). Every 3 months after the PDT, the eyes were evaluated with regard to BCVA and requirement for retreatment by fluorescein angiography (FA) with the aid of optical coherence tomography (OCT). Choroiocapillaris hypoperfusion was assessed by indocyanine green angiography (ICGA) at 3 and 12 months. All patients completed a 1-year follow-up. At the baseline, there was no difference in lesion type, size or visual acuity between the two groups. At 1 year, the change in BCVA was -0.0811 logarithm of the minimum angle of resolution (LogMAR) in the PDT-alone group, compared with -0.0432 logMAR in the PDT+TA group. There was no significant difference in the change in BCVA between the two groups (P = 0.6910). The PDT+TA group required a lower mean number of treatments (1.64 compared with 2.34 [P = 0.0223]) and showed a higher rate of choriocapillaris occlusion at 3 months, but no significant difference at 1 year (P = 0.9243) Fewer retreatments were required in the TA+PDT group. There was no significant difference in the change in BCVA between the two groups. Adjacent TA may promote short-term choriocapillaris hypoperfusion.

Combination therapy for the treatment of ocular neovascularization

The growth of inappropriately regulated, leaky blood vessels is a prominent component of several debilitating eye diseases, such as age-related macular degeneration (AMD), proliferative diabetic retinopathy (PDR), and retinopathy of prematurity (ROP). New pharmacological therapies that target vascular endothelial growth factor-A (VEGF-A) have significantly enhanced the treatment of AMD by limiting the progression of the disease, and in some cases, by improving vision. Although anti-VEGF therapy will undoubtedly prove valuable in the treatment of other neovascular diseases of the eye, improvements with this type of therapy are still required. At present, anti-VEGF therapy requires intravitreal injection and a relatively frequent dosing regimen (4-6 weeks). Furthermore, in experimental models of neovascularization, anti-VEGF treatment becomes less effective at blocking vessel growth and at regressing vessels as the neovascularization develops over time. As such, the use of anti-VEGF therapy in late-stage AMD may be limited. An important strategy for improved treatment of neovascular diseases of the eye could be combination therapy. Combination therapy of anti-VEGF drugs with established treatments, such as photodynamic therapy with verteporfin (PDT-V), or with newly-developed drugs targeting specific kinases, presents opportunities for increased efficacy and improved therapeutic outcome. In this review, we evaluate the opportunities for combination therapy for the treatment of neovascular diseases of the eye.

Intravitreal bevacizumab for exudative age-related macular degeneration after multiple treatments

Photodynamic therapy with verteporfin (PDT) significantly reduces the risk of vision loss in patients with exudative age-related macular degeneration (AMD). Indocyanine green-mediated photothrombosis (IMP) and trans-pupillary thermotherapy (TTT) may also be beneficial for selective cases of exudative AMD. However, a substantial subset of patients responds poorly to these treatments. Intravitreal bevacizumab (IVB) has been recently used in the treatment of exudative AMD, showing both visual and anatomic improvement in the majority of cases. This interventional retrospective case series reports the effects of IVB in 17 eyes with subfoveal neovascular AMD that had undergone repeated PDT (combined or not with triamcinolone acetonide) or PDT followed by either IMP or TTT with poor results. The main outcome measures were visual acuity and tomographic signs of intra/subretinal fluid, as well as central retinal thickness. Most patients received a single IVB injection. The mean follow-up was 4.47 months. The mean logMAR visual acuity changed from 1.17 +/- 0.40 to 1.06 +/- 0.44 (P = 0.17). The mean central retinal thickness decreased from 404.05 +/- 245.26 to 280.23 +/- 143.14 microm (P = 0.032). At the end of the study, lack of tomographic signs of intra/ subretinal fluid was noted in four (23.5%) eyes. No ocular or systemic side effects were identified. Short-term results with IVB for the treatment of exudative AMD have been promising. However, the chronic retinal and pigment epithelium changes frequently present in eyes that underwent multiple previous treatments may limit complete visual recovery. To our knowledge, this is the first report on the use of IVB for this particular group of AMD patients.

PHOTODYNAMIC THERAPY AND HIGH-DOSE INTRAVITREAL TRIAMCINOLONE TO TREAT EXUDATIVE AGE-RELATED MACULAR DEGENERATION

In Brief Purpose: To evaluate the efficacy of photodynamic therapy with verteporfin (PDT) and high-dose intravitreous triamcinolone acetonide to treat choroidal new vessels (CNVs) associated with age-related macular degeneration (AMD). Methods: In this prospective, consecutive, comparative, nonrandomized, interventional case series, 30 consecutive eyes of 30 patients with subfoveal CNVs associated with AMD were treated with PDT followed by the intravitreal injection of 19.4 ± 2.1 mg /0.1 mL triamcinolone 5 days later. Fifteen eyes had received no previous treatment (group 1), and 15 had been treated previously with PDT alone (group 2). A group of 15 eyes of 15 patients treated with PDT alone, matched for age and CNV composition and size, served as controls. Changes in best-corrected visual acuity (BCVA; logMAR), the number of Snellen lines improved or lost, and the number of PDT sessions were considered as primary outcome indicators. Results: Group 1 improved an average of 0.7 ± 3.7 Snellen lines (range, −5 to 10) (P = 0.62), group 2 lost an average of −0.7 ± 1.5 Snellen lines (range, −5 to 1) (P = 0.08), and the control group lost an average of −2.2 ± 0.4 Snellen lines (range, -9 to 4) (P = 0.06; Wilcoxon signed rank test). The average number of PDT treatments during the 12-month follow-up was 1.6, 1.2, and 2.8 for group 1, group 2, and the control group, respectively. Intraocular pressure rose in 8 (57%) of 14 eyes in group 1 and in 7 (50%) of 14 eyes in group 2. Cataracts developed in 4 eyes (31%) in group 1 and in 4 eyes (33%) in group 2. Conclusion: Combined PDT/intravitreal triamcinolone acetonide as treatment for AMD-associated CNVs was associated with improved final BCVA and reduced the need for retreatment compared with historical controls. Combined Photodynamic therapy followed by intravitreal triamcinolone acetonide injection at high dose (±20 mg) as treatment for AMD-associated CNVs in all lesion types was associated with improved final vision and reduced the need for retreatment rate compared to historical controls.