Carlo Incorvaia

Mechanism of Inflammation in Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is a multifactorial disease that represents the most common cause of irreversible visual impairment among people over the age of 50 in Europe, the United States, and Australia, accounting for up to 50% of all cases of central blindness. Risk factors of AMD are heterogeneous, mainly including increasing age and different genetic predispositions, together with several environmental/epigenetic factors, that is, cigarette smoking, dietary habits, and phototoxic exposure. In the aging retina, free radicals and oxidized lipoproteins are considered to be major causes of tissue stress resulting in local triggers for parainflammation, a chronic status which contributes to initiation and/or progression of many human neurodegenerative diseases such as AMD. Experimental and clinical evidences strongly indicate the pathogenetic role of immunologic processes in AMD occurrence, consisting of production of inflammatory related molecules, recruitment of macrophages, complement activation, microglial activation and accumulation within those structures that compose an essential area of the retina known as macula lutea. This paper reviews some attractive aspects of the literature about the mechanisms of inflammation in AMD, especially focusing on those findings or arguments more directly translatable to improve the clinical management of patients with AMD and to prevent the severe vision loss caused by this disease.

Inflammatory Mediators and Angiogenic Factors in Choroidal Neovascularization: Pathogenetic Interactions and Therapeutic Implications

Choroidal neovascularization (CNV) is a common and severe complication in heterogeneous diseases affecting the posterior segment of the eye, the most frequent being represented by age-related macular degeneration. Although the term may suggest just a vascular pathological condition, CNV is more properly definable as an aberrant tissue invasion of endothelial and inflammatory cells, in which both angiogenesis and inflammation are involved. Experimental and clinical evidences show that vascular endothelial growth factor is a key signal in promoting angiogenesis. However, many other molecules, distinctive of the inflammatory response, act as neovascular activators in CNV. These include fibroblast growth factor, transforming growth factor, tumor necrosis factor, interleukins, and complement. This paper reviews the role of inflammatory mediators and angiogenic factors in the development of CNV, proposing pathogenetic assumptions of mutual interaction. As an extension of this concept, new therapeutic approaches geared to have an effect on both the vascular and the extravascular components of CNV are discussed.

Light panretinal photocoagulation (LPRP) versus classic panretinal photocoagulation (CPRP) in proliferative diabetic retinopathy.

Purpose. We misled to verify whether a panretinal photocoagulation (PRP) performed using low levels of ARGON laser energy (light PRP) has the same efficacy as a PRP performed in a conventional fashion using argon green wavelengths (classic PRP) in eyes with high-risk proliferative diabetic retinopathy (HRPDR). Furthermore, we misled to compare the session number performed and the side effects produced by the two techniques. Methods. Sixty-five eyes with HRPDR of 50 consecutive patients were enrolled in a prospective randomized controlled trial. In eyes selected for light PRP, a very light biomicroscopic effect on the retina was obtained for each spot. In eyes assigned to classic PRP, each spot produced a white-yellow biomicroscopic effect. Mean follow-up was 22.4 months ±9.7 in the light PRP and 21.6 months ±9.3 in the classic PRP group (p = 0.727). Results. The initial mean logMAR visual acuity (VA) in the light PRP group was 0.12 ± 0.13 and in the classic PRP group 0.14 ± 0.15 (p = 0.493). The final mean VA in the former was 0.18 ± 0.25, and in the latter 0.27 ± 0.30 (p = 0.231). Median power was 235 mW (100–540 mW) for light and 420 mW (200–950 mW) for classic PRP (p < 0.001). Regression of HRPDR at the end of the follow-up was obtained in 30/31 eyes (97%) treated with classic PRP and in 31/34 eyes (91%) treated with light PRP (p = 0.615). The total mean session number was 7.4 ± 2.4 for light and 9.9 ± 2.2 for the classic PRP group (p < 0.001). Complications were more frequent in the classic PRP group. Conclusions. The efficacy of Light PRP is similar to that of classic Light PRP in eyes with HRPDR. Light PRP is associated with fewer complications and allows the reduction of the number of treatment sessions.

Mechanism of Inflammation in Age-Related Macular Degeneration: An Up-to-Date on Genetic Landmarks

Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment among people over 50 years of age, accounting for up to 50% of all cases of legal blindness in Western countries. Although the aging represents the main determinant of AMD, it must be considered a multifaceted disease caused by interactions among environmental risk factors and genetic backgrounds. Mounting evidence and/or arguments document the crucial role of inflammation and immune-mediated processes in the pathogenesis of AMD. Proinflammatory effects secondary to chronic inflammation (e.g., alternative complement activation) and heterogeneous types of oxidative stress (e.g., impaired cholesterol homeostasis) can result in degenerative damages at the level of crucial macular structures, that is photoreceptors, retinal pigment epithelium, and Bruchs membrane. In the most recent years, the association of AMD with genes, directly or indirectly, involved in immunoinflammatory pathways is increasingly becoming an essential core for AMD knowledge. Starting from the key basic-research notions detectable at the root of AMD pathogenesis, the present up-to-date paper reviews the best-known and/or the most attractive genetic findings linked to the mechanisms of inflammation of this complex disease.

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

Objectives 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. Methods 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. Results 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]. Conclusion 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.

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

PURPOSE 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). METHODS 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. RESULTS 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. CONCLUSIONS 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.

Parnaparin versus aspirin in the treatment of retinal vein occlusion. A randomized, double blind, controlled study

INTRODUCTION Retinal vein occlusion (RVO) is a common cause of unilateral visual loss. Evidence based treatment recommendations for patients with RVO cannot be made because of the lack of adequate clinical trials. To compare the efficacy and safety of aspirin and of a low molecular weight heparin, parnaparin, in the treatment of RVO. MATERIALS AND METHODS In a multicenter, randomized, double blind, controlled trial eligible patients with a delay between symptoms onset and objective diagnosis of less than 15 days were randomized to aspirin 100 mg/day for 3 months or to a fixed daily dose of parnaparin, 12.800 IU for 7 days followed by 6.400 IU for a total of 3 months. Primary end-point of the study was the incidence of functional worsening of the eye with RVO at 6 months, as assessed by fluorescein angiography, visual acuity, and visual field. Study end-points were adjudicated by an independent committee. RESULTS Sixty-seven patients were enrolled in the study and 58 of them (28 treated with parnaparin, 30 with aspirin) were evaluable for the analysis. Baseline characteristics were well balanced between groups. Functional worsening was adjudicated in 20.7% of patients treated with parnaparin and in 59.4% of patients treated with ASA (p=0.002). Recurrent RVO was diagnosed in 3 patients, all treated with ASA (p=n.s.). Bleeding rates were similar between the two groups. CONCLUSIONS Parnaparin appears to be more effective than aspirin in preventing functional worsening in patients with RVO. The results of this study need to be confirmed in a larger clinical trial.

Idiopathic central retinal vein occlusion in a thrombophilic patient with the heterozygous 20210 G/A prothrombin genotype

PURPOSE To report the occurrence of monolateral central retinal vein occlusion in a patient with heterozygous 20210 G/A prothrombin genotype, known to be associated with high thrombophilic risk. METHODS A monolateral central retinal vein occlusion was diagnosed in a 71-year-old woman, who had suffered from a deep vein thrombosis in her left leg at the age of 36 years. Mutations of the genes involved in the coagulation process were investigated by DNA polymerase chain reaction. RESULT DNA analysis showed the patient to be heterozygous for the prothrombin 20210 G/A genetic variation. CONCLUSION The 20210 G/A prothrombin gene mutation may be associated with central retinal vein occlusion.

Local and systemic inoculation of DNA or protein gB1s-based vaccines induce a protective immunity against rabbit ocular HSV-1 infection

A secreted form of gB1 (gB1s), previously shown to protect rabbits against HSV-1 ocular infection when inoculated systemically, was delivered to rabbit periocular area to evaluate its vaccine efficacy upon local administration. The efficacy of local or systemic inoculation of a gB1s-DNA-based vaccine in the rabbit model of ocular HSV-1 infection was assessed in parallel flow. Rabbits received four inoculations of the different immunogens, then immune responses and clinical symptoms were evaluated. Both the local protein and the systemic DNA administration elicited a neutralizing antibody response, reduced ocular symptoms with respect to controls (P<0.01), and completely prevented the death of rabbits from encephalitis. Conversely, local DNA vaccination did not induce any detectable antibody response, and could only partially protect rabbits from the development of encephalitis and severe ocular infection.

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.