Paolo Perri

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.

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.

The importance of glial cells in the homeostasis of the retinal microenvironment and their pivotal role in the course of diabetic retinopathy

Diabetic retinopathy (DR) is a remarkable microvascular complication of diabetes and it has been considered the leading cause of legal blindness in working-age adults in the world. Several overlapping and interrelated molecular pathways are involved in the development of this disease. DR is staged into different levels of severity, from the nonproliferative to the advanced proliferative form. Over the years the progression of DR evolves through a series of changes involving distinct types of specialized cells: neural, vascular and glial. Prior to the clinically observable vascular complications, hyperglycemia and inflammation affect retinal glial cells which undergo a wide range of structural and functional alterations. In this review, we provide an overview of the status of macroglia and microglia in the course of DR, trying to briefly take into account the complex biochemical mechanisms that affect the intimate relationship among neuroretina, vessels and glial cells.

Mesectodermal leiomyoma exclusively involving the posterior choroid

PURPOSE To report a mesectodermal leiomyoma of the posterior choroid. DESIGN Observational case report. METHODS A 23-year-old man was referred to us because of a progressive blurred vision in his left eye. Ophthalmologic examination revealed the presence of a 12 x 10 x 7.2-mm amelanotic choroidal mass in his left posterior pole. Fluorescein angiography, A-scan ultrasonography, and B-scan echography findings were suggestive for a diagnosis of choroidal amelanotic melanoma. These clinical features prompted us to enucleate the left eye. RESULTS Histopathological and immunohistochemistry examinations established a definitive diagnosis of mesectodermal leiomyoma of the posterior choroid. CONCLUSION This case represents the first report describing the occurrence of an intraocular mesectodermal leiomyoma that may exclusively involve the posterior choroid.

Endogenous Aspergillus versicolor Endophthalmitis in an Immuno-competent HIV-positive Patient

A 25-year-old white, HIV-positive, immuno-competent man was referred to us because of a progressive blurred vision in his right eye. Clinical characteristics were suggestive for an unilateral fungal endophthalmitis, and thereby fluconazole firstly, followed by conventional amphotericin B were intravenously administered, without any significant improvement. Thus, a pars plana vitrectomy was performed. Aspergillus versicolor was isolated from the cultures of the vitreous sample and intravenous liposomal amphotericin B was administered. An increase of visual acuity together with a reduction of vitreous inflammation occurred. This case of ours represents the first report describing an endogenous endophthalmitis induced by Aspergillus versicolor.

Clear Cell Renal Cell Carcinoma Associated with Bilateral Atypical Acute Posterior Multifocal Placoid Pigment Epitheliopathy

Background/Objective: Clear cell renal cell carcinoma (CCRCC) is a malignant neoplasm frequently associated with an increase in circulating immune complexes (CIC). Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is a disease involving the chorioretinal structures of the eye, and it is commonly observed in association with several immunogenic disorders. We report here the clinical association between humoral immunologic modifications during tumoral diseases (long-standing CIC increase) and chorioretinal changes resembling atypical APMPPE. Case Report: A 52-year-old white male affected by metastatic CCRCC is described. Histopathologic review of his surgically removed organs (kidney and lung), periodical laboratory immunologic tests and ophthalmologic examinations, including fluorescein and indocyanine green angiographies, were performed. Results: The patient underwent total left nephrectomy (May 1997) and total left pneumonectomy (March 2001) for the presence of stage III CCRCC and CCRCC lung metastasis, respectively. On both occasions, postoperative immunotherapy was started. From June 1997 to February 2003, laboratory analyses demonstrated the presence of marked CIC peaks. During the follow-up period, an atypical APMPPE pattern, complicated by asynchronous choroidal neovascularization, occurred in both eyes. Conclusions: Long-standing tumorous disease, through a pathogenic mechanism triggered by CIC spreading, can be responsible, over time, for a progressive choroidal occlusive microangiopathy (atypical APMPPE pattern), associated with a high risk of poor visual outcome. Therefore, bilateral APMPPE could be related to a systemic disease able to increase CIC levels.

Standardized echography, pattern electroretinography and visual-evoked potential and automated perimetry in the early diagnosis of Graves' neuropathy

Twenty-four patients (47 eyes) affected by Graves’ disease were enrolled to evaluate the role of standardized echography, pattern electroretinogram (P-ERG), visual evoked potentials (P-VEPs) and automated perimetry in the early diagnosis of the compressive optic neuropathy (CON). The P-ERG amplitude reduction was the most sensitive parameter to demonstrate an early impairment of the optic nerve (ON) function. We found a significant negative correlation between the ON diameter and the P-ERG amplitude. VEPs responses were also altered, but their ability in detecting an early ON damage was less sensitive and specific than P-ERG. The visual field damage was often aspecific and delayed with respect to electrophysiological alterations.

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

PURPOSE 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). DESIGN Retrospective, consecutive, nonrandomized, interventional cases series. PARTICIPANTS Two hundred thirty-four patients exclusively treated with standardized PDT-V for the presence of PM-related classic CNV. METHODS 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. MAIN OUTCOME MEASURES 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 (patients age, baseline visual acuity, and baseline CNV area) and genotypic (all the mentioned mutations) variables regarding PDT-V efficacy. RESULTS 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 patients 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. CONCLUSIONS 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.