Francesco Semeraro

Effect of Ginkgo biloba extract on preexisting visual field damage in normal tension glaucoma

OBJECTIVE To evaluate the effect of Ginkgo biloba extract (GBE) on preexisting visual field damage in patients with normal tension glaucoma (NTG). DESIGN Prospective, randomized, placebo-controlled, double-masked cross-over trial. PARTICIPANTS Twenty-seven patients with bilateral visual field damage resulting from NTG. INTERVENTION Patients received 40 mg GBE, administered orally, three times daily for 4 weeks, followed by a wash-out period of 8 weeks, then 4 weeks of placebo treatment (identical capsules filled with 40 mg fructose). Other patients underwent the same regimen, but took the placebo first and the GBE last. Visual field tests, performed at baseline and at the end of each phase of the study, were evaluated for changes. MAIN OUTCOME MEASURES Change in visual field and any ocular or systemic complications. RESULTS After GBE treatment, a significant improvement in visual fields indices was recorded: mean deviation (MD) at baseline versus MD after GBE treatment, 11.40 +/- 3.27 dB versus 8.78 +/- 2.56 dB (t = 8.86, P = 0.0001, chi-square test); corrected pattern standard deviation (CPSD) at baseline versus CPSD after GBE treatment, 10.93 +/- 2.12 dB versus 8.13 +/- 2.12 dB (t = 9.89, P = 0.0001, chi-square test). No significant changes were found in intraocular pressure, blood pressure, or heart rate after placebo or GBE treatment. Any ocular and systemic side effects were recorded for the duration of the trial. CONCLUSIONS Ginkgo biloba extract administration appears to improve preexisting visual field damage in some patients with NTG.

Diabetic Retinopathy: Vascular and Inflammatory Disease

Diabetic retinopathy (DR) is the leading cause of visual impairment in the working-age population of the Western world. The pathogenesis of DR is complex and several vascular, inflammatory, and neuronal mechanisms are involved. Inflammation mediates structural and molecular alterations associated with DR. However, the molecular mechanisms underlying the inflammatory pathways associated with DR are not completely characterized. Previous studies indicate that tissue hypoxia and dysregulation of immune responses associated with diabetes mellitus can induce increased expression of numerous vitreous mediators responsible for DR development. Thus, analysis of vitreous humor obtained from diabetic patients has made it possible to identify some of the mediators (cytokines, chemokines, and other factors) responsible for DR pathogenesis. Further studies are needed to better understand the relationship between inflammation and DR. Herein the main vitreous-related factors triggering the occurrence of retinal complication in diabetes are highlighted.

Novel aspects of Sjögren’s syndrome in 2012

Sjögren’s syndrome (SS) is a systemic progressive autoimmune disease characterized by a complex pathogenesis requiring a predisposing genetic background and involving immune cell activation and autoantibody production. The immune response is directed to the exocrine glands, causing the typical ‘sicca syndrome’, but major organ involvement is also often seen. The etiology of the disease is unknown. Infections could play a pivotal role: compared to normal subjects, patients with SS displayed higher titers of anti-Epstein-Barr virus (EBV) early antigens, but lower titers of other infectious agent antibodies such as rubella and cytomegalovirus (CMV) suggest that some infections may have a protective role against the development of autoimmune disease. Recent findings seem to show that low vitamin D levels in patients with SS could be associated with severe complications such as lymphoma and peripheral neuropathy. This could open new insights into the disease etiology. The current treatments for SS range from symptomatic therapies to systemic immunosuppressive drugs, especially B cell-targeted drugs in cases of organ involvement. Vitamin D supplementation may be an additional tool for optimization of SS treatment.

Color Doppler imaging of ophthalmic artery blood flow velocity: A study of repeatability and agreement

PURPOSE Color Doppler imaging (CDI) is a relatively new technique that allows quantification of blood flow velocity in orbital and ocular vasculature. Despite the numerous clinical studies that have used CDI, repeatability of this technique and agreement between observers have not been documented. METHODS The authors performed a prospective investigation of the repeatability and agreement between observers on ophthalmic artery blood flow velocity measurements in 35 patients (35 eyes). RESULTS Results on the estimated error of measurement (variability between repeated readings on the same subject) indicate good repeatability of the measurements; in fact, the measurement variances were only 5.6% for the peak systolic velocity, 11.4% for the end diastolic velocity, and 6.2% for the mean envelope velocity. The statistical analysis of repeatability showed a very narrow 95% confidence interval for both observers. The measurement of agreement between the two observers demonstrated the existence of a good concordance of the measurements taken by each observer on each subject. CONCLUSIONS Results suggest that CDI is a reliable tool for quantitative assessment of ophthalmic artery blood flow velocity.

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.

Relationship between media-to-lumen ratio of subcutaneous small arteries and wall-to-lumen ratio of retinal arterioles evaluated noninvasively by scanning laser Doppler flowmetry.

Background: Structural alterations of subcutaneous small resistance arteries, as indicated by an increased media-to-lumen ratio, are frequently present in hypertensive and/or diabetic patients, and may represent the earliest alteration observed. Furthermore, media-to-lumen ratio of small arteries evaluated by micromyography has a strong prognostic significance; however, its extensive evaluation is limited by the invasivity of the assessment, since a biopsy of subcutaneous fat is needed. Noninvasive measurement of wall-to-lumen of retinal arterioles using scanning laser Doppler flowmetry (SLDF) has recently been introduced. However, this new technique has not yet been compared to micromyographic measurement, generally considered the gold standard approach. Methods and results: We investigated 40 individuals and patients, 24 of them were hypertensive patients and 16 normotensive individuals. All patients underwent a biopsy of subcutaneous fat during an elective surgical intervention. Subcutaneous small resistance arteries were dissected and mounted on a wire myograph, and media-to-lumen ratio was measured. In addition, an evaluation of wall-to-lumen ratio of retinal arterioles by SLDF was performed (Heidelberg Retina Flowmeter, Heidelberg Engineering). A close correlation was observed between media-to-lumen ratio of subcutaneous small arteries and wall-to-lumen ratio of retinal arterioles (r = 0.76, P < 0.001; P < 0.001, r2 = 0.57). Conclusion: A noninvasive and easily repeatable procedure (intraobserver and interobserver variation coefficient <13%) such as an evaluation of the arterioles in the fundus oculi by SLDF may provide similar information regarding microvascular morphology compared with an invasive, accurate and prognostically relevant micromyographic measurement of media-to-lumen ratio of subcutaneous small arteries.

Aflibercept in wet AMD: specific role and optimal use

Background Vascular endothelial growth factor (VEGF) is a naturally occurring glycoprotein in the body that acts as a growth factor for endothelial cells. It regulates angiogenesis, enhances vascular permeability, and plays a major role in wet age-related macular degeneration. The consistent association between choroidal neovascularization and increased VEGF expression provides a strong reason for exploring the therapeutic potential of anti-VEGF agents in the treatment of this disorder. Blockade of VEGF activity is currently the most effective strategy for arresting choroidal angiogenesis and reducing vascular permeability, which is frequently the main cause of visual acuity deterioration. In recent years, a number of other molecules have been developed to increase the efficacy and to prolong the durability of the anti-VEGF effect. Aflibercept (EYLEA®; Regeneron Pharmaceutical Inc and Bayer), also named VEGF Trap-eye, is the most recent member of the anti-VEGF armamentarium that was approved by the US Food and Drug Administration in November 2011. Because of its high binding affinity and long duration of action, this drug is considered to be a promising clinically proven anti-VEGF agent for the treatment of wet maculopathy. Objective This article reviews the current literature and clinical trial data regarding the efficacy and the pharmacological properties of VEGF-Trap eye and describes the possible advantages of its use over the currently used “older” anti-VEGF drugs. Methods For this review, a search of PubMed from January 1989 to May 2013 was performed using the following terms (or combination of terms): vascular endothelial growth factors, VEGF, age-related macular degeneration, VEGF-Trap eye in wet AMD, VEGF-Trap eye in diabetic retinopathy, VEGF-Trap eye in retinal vein occlusions, aflibercept. Studies were limited to those published in English. Results and conclusion Two Phase III clinical trials, VEGF Trap-eye Investigation of Efficacy and Safety in Wet AMD (VIEW) 1 and 2, comparing VEGF Trap-eye to ranibizumab demonstrated the noninferiority of this novel compound. The clinical equivalence of this compound against ranibizumab is maintained even when the injections are administered at 8-week intervals, which indicates the potential to reduce the risk of monthly intravitreal injections and the burden of monthly monitoring.

Comparison of Smartphone Ophthalmoscopy With Slit-Lamp Biomicroscopy for Grading Diabetic Retinopathy

PURPOSE To assess the accuracy and reliability of smartphone ophthalmoscopy, we compared the ability of a smartphone ophthalmoscope with that of a slit-lamp biomicroscope to grade diabetic retinopathy (DR) in patients with diabetes mellitus (DM). DESIGN Clinical-based, prospective, comparative instrument study. METHODS This comparative clinical study was performed in 120 outpatients (240 eyes) with type 1 or type 2 DM. After pupil dilation, the patients underwent smartphone ophthalmoscopy with the D-Eye device, followed by dilated retinal slit-lamp examination, to grade DR according to a 5-step scale. RESULTS Overall exact agreement between the 2 methods was observed in 204 of 240 eyes (85%) (simple κ = 0.78; CI 0.71-0.84) and agreement within 1 step was observed in 232 eyes (96.7%). Compared to biomicroscopy, the sensitivity and specificity of smartphone ophthalmoscopy for the detection of clinically significant macular edema were 81% and 98%, respectively. Smartphone ophthalmoscopy and biomicroscopy could not be used to examine the fundus and grade DR in 9 eyes (3.75%) and 4 eyes (1.7%), respectively, because of cataract and/or small pupil diameter. CONCLUSION Smartphone ophthalmoscopy showed considerable agreement with dilated retinal biomicroscopy for the grading of DR. The portability, affordability, and connectivity of a smartphone ophthalmoscope make smartphone ophthalmoscopy a promising technique for community screening programs.

Systemic thromboembolic adverse events in patients treated with intravitreal anti-VEGF drugs for neovascular age-related macular degeneration

Introduction: The consistent association between choroid neovascularization (CNV) and increased VEGF-A expression provides a strong reason for exploring the therapeutic potential of anti-VEGF agents in the treatment of neovascular age-related macular degeneration (AMD). The authors report the systemic side effects secondary to intravitreal administration of these compounds, that is, the main cardiovascular effects, as well as the less frequent cerebrovascular accidents, myocardial infarction, transient ischemic attacks, deep vein thrombosis, pulmonary embolism and thromboflebitis. Areas covered: The authors reviewed major Clinical Trials and publications concerning systemic adverse events of anti-VEGF drugs in order to identify the main thromboembolic events related to the use of these agents and their occurrence. Anti-VEGF efficacy, safety and tolerability are also discussed. Expert opinion: Three compounds (pegaptanib, ranibizumab and aflibercept) have been approved for the treatment of AMD; a fourth agent, bevacizumab, is used off-label. Anti-VEGF therapy has not shown the ability to fully eradicate the CNV, so that recurrences are common when the intravitreal injections are suspended. Although no evident rise in anti-VEGF-induced thromboembolic side effects was reported, more data are required to evaluate hemodynamic and pharmacokinetics of these compounds. Since only few studies have focused on these aspects, further researches are mandatory to determine distribution, effects and duration of these substances.

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.