Adolfo Sebastiani

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.

Good epidemiologic practice in retinitis pigmentosa: from phenotyping to biobanking.

Inherited retinal dystrophies, such as retinitis pigmentosa (RP), include a group of relatively rare hereditary diseases caused by mutations in genes that code for proteins involved in the maintenance and function of the photoreceptor cells (cones and rods). The different forms of RP consist of progressive neurodegenerative disorders which are generally related to various and severe limitations of visual performances. In the course of typical RP (rod-cone dystrophy), the affected individuals first experience night-blindness and/or visual field constriction (secondary to rod dysfunctions), followed by variable alterations of the central vision (due to cone damages). On the other hand, during the atypical form of RP (cone-rod dystrophy), the cone’s functionalities are prevalently disrupted in comparison with the rod’s ones. The basic diagnosis of RP relies upon the documentation of unremitting loss in photoreceptor activity by electroretinogram and/or visual field testing. The prevalence of all RP typologies is variably reported in about one case for each 3000-5000 individuals, with a total of about two millions of affected persons worldwide. The inherited retinal dystrophies are sometimes the epiphenomenon of a complex framework (syndromic RP), but more often they represent an isolated disorder (about 85-90 % of cases). Although 200 causative RP mutations have been hitherto detected in more than 100 different genes, the molecular defect is identifiable in just about the 50% of the analyzed patients with RP. Not only the RP genotypes are very heterogeneous, but also the patients with the same mutation can be affected by different phenotypic manifestations. RP can be inherited as autosomal dominant, autosomal recessive or X-linked trait, and many sporadic forms are diagnosed in patients with no affected relatives. Dissecting the clinico-genetic complexity of RP has become an attainable objective by means of large-scale research projects, in which the collaboration between ophthalmologists, geneticists, and epidemiologists becomes a crucial aspect. In the present review, the main issues regarding clinical phenotyping and epidemiologic criticisms of RP are focused, especially highlighting the importance of both standardization of the diagnostic protocols and appropriateness of the disease’s registration systems.

SSRIs and intraocular pressure modifications: evidence, therapeutic implications and possible mechanisms.

SSRIs are the most commonly prescribed antidepressant drugs, in part because of their favourable safety profile compared with older antidepressants. However, the widespread use of SSRIs leads to an increased occurrence of rare adverse effects. This review, based on data from published experimental research, clinical studies and case reports, describes the role of serotonin in the control of intraocular pressure (IOP) and the evidence for IOP modifications in patients receiving SSRIs.In a small percentage of patients with depression, the cause of SSRI withdrawal has been the occurrence of ill-defined visual disturbances. It can be speculated that in some of these patients, the iatrogenic ocular alterations could have been due to changes in IOP. There have also been a limited number of case reports of acute attacks of glaucoma occurring during treatment with SSRIs. Although causality is not exactly specified, the relationship between SSRIs and this ocular adverse event is strongly implied. Nevertheless, in a small clinical study assessing the effect of a single dose of fluoxetine on IOP, the drug was shown to increase this parameter, although the effect was asymptomatic. The clinical signs of unexpected adverse drug effects are often disregarded, with the exception of those characterised by serious symptoms (such as acute angle-closure glaucoma in the case of IOP modifications). Also, the distribution of iridocorneal angle configurations in the general population implies that an adverse effect on IOP will be paucior asymptomatic in most patients (intermittent, sub-acute or progressive angle-closure glaucoma). As a result, it is likely that the incidence of SSRI-related IOP modifications is underestimated.Until the involvement of SSRIs in IOP modifications is better understood, ophthalmological consultations should be considered before starting and during treatment with any SSRI in patients with glaucomatous risk factors, especially those who are elderly.

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.

Selective serotonin reuptake inhibitors: a review of its effects on intraocular pressure.

The increase in serotonin (5-HT) neurotransmission is considered to be one of the most efficacious medical approach to depression and its related disorders. The selective serotonin reuptake inhibitors (SSRIs) represent the most widely antidepressive drugs utilized in the medical treatment of depressed patients. Currently available SSRIs include fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram and escitalopram. The primary SSRIs pharmacological action’s mechanism consists in the presynaptic inhibition on the serotonin reuptake, with an increased availability of this amine into the synaptic cleft. Serotonin produces its effects as a consequence of interactions with appropriate receptors. Seven distinct families of 5-HT receptors have been identified (5-HT1 to 5-HT7), and subpopulations have been described for several of these. The interaction between serotonin and post-synaptic receptors mediates a wide range of functions. The SSRIs have a very favorable safety profile, although clinical signs of several unexpected pathologic events are often misdiagnosed, in particular, those regarding the eye. In all cases reported in the literature the angle-closure glaucoma represents the most important SSRIs-related ocular adverse event. Thus, it is not quite hazardous to hypothesize that also the other reported and unspecified visual disturbances could be attributed - at least in some cases - to IOP modifications. The knowledge of SSRIs individual tolerability, angle-closure predisposition and critical IOP could be important goals able to avoid further and more dangerous ocular side effects.

Effect of hinged lamellar keratotomy on postkeratoplasty eyes 1

PURPOSE To evaluate the effect of a hinged lamellar keratotomy on refraction, vision, and corneal topography of postkeratoplasty eyes with high-degree astigmatism. DESIGN Noncomparative, interventional case series. PARTICIPANTS A hinged lamellar keratotomy was performed on nine eyes of nine patients at least 9 months after penetrating keratoplasty and with high-degree astigmatism. All patients were spectacle and contact lens intolerant. INTERVENTION A superiorly hinged lamellar keratotomy (corneal flap), 160 microm in thickness and 9 mm in diameter, was created on all eyes included in this study. Each patient was examined 1 day, 1 month, and 3 months after surgery. MAIN OUTCOME MEASURES Uncorrected visual acuity, best spectacle-corrected visual acuity, refraction, computerized analysis of corneal topography. RESULTS At each postoperative examination time, there was a significant reduction in both average spherical equivalent (P < 0.05) and average absolute value of astigmatism (P < 0.01) over mean preoperative values. The major changes were seen as early as 1 day after surgery, but both progression and regression of the effect were documented at later postoperative examinations. In all patients best spectacle-corrected acuity was maintained or improved after the procedure. Postoperatively, four patients could be successfully corrected either with spectacles (n = 2) or with gas-permeable contact lenses (n = 2). There were no surgical flap or corneal graft complications. CONCLUSIONS Hinged lamellar keratotomy improves vision and refraction of postkeratoplasty eyes with high-degree astigmatism. In some cases it may be so effective as to make planned excimer laser treatment unnecessary.

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.

Non-Contact Tonometry in Patients that Underwent Photorefractive Keratectomy

To determine the accuracy of non-contact tonometry in patients with corneas thinned by photorefractive keratectomy, the authors measured the intraocular pressure with a non-contact tonometer and the corneal thickness with an ultrasonic pachymeter in 47 patients before and 9 months after photorefractive keratectomy. The patients were divided into three groups according to the degree of treatment: group I between 1 and 5 diopters (14 eyes), group II between 6 and 10 diopters (18 eyes), group III between 11 and 15 diopters (15 eyes). In the first group of patients mean intraocular pressure was 16.1 (+/-3.85) mm Hg before surgery, and 13.2 (+/-3.14) mm Hg after surgery with a significant difference (p = 0.0027). In the second group of patients mean intraocular pressure was 16.0 (+/-4.13) mm Hg before surgery and 13.0 (+/-3.0) mm Hg after surgery with a significant difference (p = 0.0045). In the third group of patients mean intraocular pressure was 17.7 (+/-3.8) mm Hg before surgery and 12.4 (+/-2.6) mm Hg after surgery, with a significant difference (p = 0.0005). In conclusion, according to our results, non-contact tonometry needs a correcting factor for measuring the intraocular pressure in patients that underwent photorefractive keratectomy, related to the degree of refractive treatment.

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.