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Purpose This study aims to evaluate whether the use of citicoline oral solution could improve quality of life in patients with chronic open-angle glaucoma (OAG). Design Randomized, double-masked, placebo-controlled, cross-over study was used. Patients were randomized to one of the two sequences: either citicoline 500 mg/day oral solution-placebo or placebo-citicoline 500 mg/day oral solution. Switch of treatments was done after 3 months; patients were then followed for other 6 months. Follow-up included 3-month, 6-month, and 9-month visits. Outcomes The primary outcome was the mean change of “intra-patient” composite score of the Visual Function Questionnaire-25 (VFQ-25). after citicoline oral solution vs placebo at 6-month visit as compared with baseline. Methods The trial was multicenter, conducted at 5 European Eye Clinics. OAG patients with bilateral visual field damage, a mean deviation (MD) ranging from − 5 to − 13 dB in the better eye, and controlled IOP were included. VFQ-25 and SF-36 questionnaires were administered at baseline and at 3-, 6-, and 9-month visits. A mixed effect model, with a random effect on the intercept, accounted for correlations among serial measurements on each subject. Results The primary pre-specified outcome of the analysis reached statistical significance (p = 0.0413), showing greater improvement after citicoline oral solution. There was an increase in the composite score in both arms compared to baseline, but it was significant only for the placebo-citicoline arm (p = 0.0096, p = 0.0007, and p = 0.0006 for the three time-points compared to baseline). The effect of citicoline was stronger in patients with vision-related quality of life more affected by glaucoma at baseline. Conclusions This is the first placebo-controlled clinical study evaluating the effect of a medical treatment aiming at improving vision-related quality of life in glaucomatous patients.

Glaucoma patients often suffer from ocular surface disease (OSD) caused by the chronic administration of topical anti-glaucoma medications, especially in cases of long-term therapy with preserved or multiple drugs. Additionally, glaucoma surgery may determine ocular surface changes related to the formation and location of the filtering bleb, the application of anti-mitotic agents, and the post-operative wound-healing processes within the conjunctiva. Recently, several studies have evaluated the role of advanced diagnostic imaging technologies such as in vivo confocal microscopy (IVCM) and anterior segment-optical coherence tomography (AS-OCT) in detecting microscopic and macroscopic features of glaucoma therapy-related OSD. Their clinical applications are still being explored, with recent particular attention paid to analyzing the effects of new drug formulations and of minimally invasive surgical procedures on the ocular surface status. In this review, we summarize the current knowledge about the main changes of the ocular surface identified at IVCM and AS-OCT in glaucoma patients under medical therapy, or after surgical treatment.

Steroid-induced glaucoma is a severe pathological condition, sustained by a rapidly progressive increase in intraocular pressure (IOP), which is diagnosed in a subset of subjects who adhere to a glucocorticoid (GC)-based therapy. Molecular and clinical studies suggest that either natural or synthetic GCs induce a severe metabolic dysregulation of Trabecular Meshwork Cells (TMCs), an endothelial-derived histotype with phagocytic and secretive functions which lay at the iridocorneal angle in the anterior segment of the eye. Since TMCs physiologically regulate the composition and architecture of trabecular meshwork (TM), which is the main outflow pathway of aqueous humor, a fluid which shapes the eye globe and nourishes the lining cell types, GCs are supposed to trigger a pathological remodeling of the TM, inducing an IOP increase and retina mechanical compression. The metabolic dysregulation of TMCs induced by GCs exposure has never been characterized at the molecular detail. Herein, we report that, upon dexamethasone exposure, a TMCs strain develops a marked inhibition of the autophagosome biogenesis pathway through an enhanced turnover of two members of the Ulk-1 complex, the main platform for autophagy induction, through the Ubiquitin Proteasome System (UPS).

To evaluate the retinal function and the relative neural conduction along the visual pathway after treatment with citicoline in liposomal formulation (CLF) eye drops in patients with open angle glaucoma (OAG). Twelve OAG patients (mean age ± standard deviation 52.58 ± 11.39 years, intraocular pressure

Cytidine 5’-diphosphocholine has been widely studied in systemic neurodegenerative diseases, like Alzheimer’s disease, Parkinson’s disease, and brain ischemia. The rationale for the use of citicoline in ophthalmological neurodegenerative diseases, including glaucoma, anterior ischemic optic neuropathy, and diabetic retinopathy, is founded on its multifactorial mechanism of action and the involvement in several metabolic pathways, including phospholipid homeostasis, mitochondrial dynamics, as well as cholinergic and dopaminergic transmission, all being involved in the complexity of the visual transmission. This narrative review is aimed at reporting both pre-clinical data regarding the involvement of citicoline in such metabolic pathways (including new insights about its role in the intracellular proteostasis through an interaction with the proteasome) and its effects on clinical psychophysical, electrophysiological, and morphological outcomes following its use in ophthalmological neurodegenerative diseases (including the results of the most recent prospective randomized clinical trials).

Precis Citicoline eyedrops in patients with progressing glaucoma. Purpose This study aimed to test whether the additional therapy with citicoline eyedrops to intraocular pressure (IOP)-lowering treatment could slow glaucoma progression in patients with worsening of damage and IOP 18 mm Hg or less. Design This was a randomized, double-masked, placebo-controlled, multicenter 3-year study. Outcomes The outcomes studied were difference in the visual field (mean deviation, MD, of 24-2; MD of 10-2) rates of progression and difference in retinal nerve fiber layer (RNFL) thickness change between the 2 study groups at 3 years. Methods Patients with mild to moderate open-angle glaucoma (OAG) showing damage progression of at least -0.5 dB/y in the 2 years before enrollment despite IOP ≤18 mm Hg were randomized to receive citicoline eyedrops or placebo 3 times daily for 3 years. Patients were followed every 3 months and underwent a visual field examination with 24-2 and 10-2 strategies and RNFL assessment. Analysis of variance and linear models were used to test the differences between groups. Results Eighty patients were randomized in the trial. The mean 3-year rates of progression were -1.03 (2.14) dB in the citicoline group and -1.92 (2.23) dB in the placebo group (P=0.07) for 24-2 MD and -0.41 (3.45) dB in the citicoline group and -2.22 (3.63) dB in the placebo group (P=0.02) for 10-2 MD. On average, patients receiving citicoline eyedrops lost 1.86 μm of RNFL in 3 years, versus 2.99 μm in the placebo group (P=0.02). Conclusions Additional treatment with citicoline eyedrops to IOP-lowering treatment might reduce disease progression in patients with progressing glaucoma despite IOP ≤18 mm Hg.

Citicoline or CDP-choline is a drug, made up by a cytidine 5′-diphosphate moiety and choline, which upon adsorption is rapidly hydrolyzed into cytidine 5′-diphosphate and choline, easily bypassing the blood–brain barrier. Once in the brain, these metabolites are used to re-synthesize citicoline in neurons and in the other cell histo-types which uptake them. Citicoline administration finds broad therapeutic application in the treatment of glaucoma as well as other retinal disorders by virtue of its safety profile and neuro-protective and neuroenhancer activity, which significantly improves the visual function. Further, though supported by limited clinical studies, this molecule finds therapeutic application in neurodegenerative disease, delaying the cognitive decline in Alzheimer's Disease (AD) and Parkinson's Disease (PD) subjects. In this work we show that citicoline greatly affects the proteolytic activity of the 20S proteasome on synthetic and natural substrates, functioning as a bimodal allosteric modulator, likely binding at multiple sites. In silico binding simulations identify several potential binding sites for citicoline on 20S proteasome, and their topology envisages the possibility that, by occupying some of these pockets, citicoline may induce a conformational shift of the 20S proteasome, allowing to sketch a working hypothesis for the structural basis of its function as allosteric modulator. In addition, we show that over the same concentration range citicoline affects the distribution of assembled proteasome populations and turn-over of ubiquitinated proteins in SH-SY5Y and SK-N-BE human neuroblastoma cells, suggesting its potential role as a regulator of proteostasis in nervous cells.

Neurodegeneration can be defined as progressive cell damage to nervous system cells, and more specifically to neurons, which involves morphologic alterations and progressive loss of function until cell death. Glaucoma exhibits many aspects of neurodegenerative disease. This review examines the pathogenesis of glaucoma, comparing it with that of Alzheimer's disease (AD) and Parkinson's disease (PD), highlighting their common features. Indeed, in all three diseases there are not only the same types of pathogenic events, but also similarities of temporal cadences that determine neuronal damage. All three age-related illnesses have oxidative damage and mitochondrial dysfunction as the first pathogenic steps. The consequence of these alterations is the death of visual neurons in glaucoma, cognitive neurons in AD and regulatory motor neurons (substantia nigra) in PD. The study of these common pathogenic events (oxidative stress, mitochondrial dysfunction, protein degradation, apoptosis and autophagy) leads us to consider common therapeutic strategies for the treatment and prevention of these diseases. Also, examination of the genetic aspects of the pathways involved in neurodegenerative processes plays a key role in shedding light on the details of pathogenesis and can suggest new treatments. This review discusses the common molecular aspects involved in these three oxidative-stress and age-related diseases.

Alzheimer’s disease (AD) is a neurodegenerative disorder, which is likely to start as mild cognitive impairment (MCI) several years before its full-blown clinical manifestation. In the last two decades, optical coherence tomography (OCT) has been used to observe a significant loss in peripapillary retinal nerve fiber layer (RNFL) and in macular thickness and volume in patients affected by a form of mild to severe dementia. These morphological abnormalities correlate to some extent with the severity of the disease as evaluated with neuropsychological tests. Furthermore, these structural measures correlate with electrophysiological parameters of pattern electroretinogram, reflecting integrity of the innermost retinal layers, but not with those of the visual evoked potentials, reflecting activity of the post-chiasmatic visual pathway. The latter evidence suggests that RNFL thickness reduction is related to neuronal degeneration in the ganglion cell layer and not to a retrograde degeneration from the post-chiasmatic visual pathway. These data suggest a possible role of OCT in monitoring the progression of AD and in assessing the effectiveness of purported AD treatments.

Glucocorticoids are a class of anti-inflammatory drugs commonly used to treat various ocular and systemic conditions. Although the role of glucocorticoids in the treatment of numerous serious inflammatory diseases is pivotal, their prolonged use may increase intraocular pressure resulting in steroid-induced glaucoma. We provide a detailed update on steroid-induced glaucoma as a preventable cause of blindness in the adult and pediatric population and describe its epidemiology, social impact, and risk factors. Furthermore, we explore the propensity of different steroids to increase the intraocular pressure, the role of different routes of steroid administration, dosage and duration of treatment, as well as the clinical features, genetics, and management of steroid-induced glaucoma.

AimsTo explore the gap between diagnostic research outputs and clinical use of optical coherence tomography (OCT) in glaucoma and assess the reliability of a specific reference database when applied to a morphological imaging parameter for diagnostic purposes.MethodsConsecutive subjects enrolled in the Multicenter Italian Glaucoma Imaging Study (MIGIS) have been included in this cross-sectional, comparative evaluation of diagnostic tests study. Patients underwent measurement of global and sectorial peripapillary retinal nerve fibre thickness (pRNFL) and minimum rim width (MRW) by OCT. The sensitivity and specificity of reference-database categorical classifications were calculated by means of 2×2 tables and sensitivity was compared with that of the corresponding continuous parameter extracted from the receiver operating characteristic (ROC) curves by matching the specificity.Results280 Caucasian subjects have been included. At matched specificities, the sensitivity of pRNFL categorical classifications was statistically similar to that of the corresponding continuous parameters, whereas the sensitivity of the MRW categorical classifications was significantly lower than that of the corresponding continuous parameters.ConclusionsThe diagnostic accuracy of reference database classifications might be lower than that extrapolated from the ROC curves of continuous parameters used in diagnostic research. The gap between the accuracy of these two approaches may be used to estimate the reliability of a specific reference database when applied to a continuous parameter for diagnostic purposes.

Ocular surface disease is characterized by tear film instability and histopathologic and clinical changes of the ocular surface. Glaucoma patients often suffer from ocular surface disease caused by the chronic use of preserved medical treatment to reduce intraocular pressure. Benzalkonium chloride is the preservative most frequently used in glaucoma medications. Its effect on tear film, conjunctiva and cornea and the consequences in glaucoma management are discussed in this mini-review.

Purpose To evaluate the presence and concentration of citicoline and its metabolites (choline, cytidine and uridine) in the vitreous body in human eyes after topical application of an ophthalmic solution of citicoline 2%, in vivo. Methods Twenty-one subjects affected by epiretinal membrane with surgical indication for pars-plana vitrectomy underwent treatment with 1 drop 3 times/day of a solution of citicoline 2%, 0.2% high molecular weight hyaluronic acid and 0.01% benzalkonium chloride (OMK1, Omikron Italia s.r.l., Rome, Italy) 14 days before surgery and 2 hours prior to surgery. Five additional patients served as controls and received an OMK1 vehicle solution without citicoline. The vitreous samples were taken at the beginning of the pars-plana vitrectomy and analyzed for qualitative/quantitative determination of vitreous concentration of citicoline and its metabolites by means of high performance liquid chromatography. Results The overall mean concentration of citicoline in patients treated with citicoline 2% solution was 406.72 ± 52.99 μg/mL, while the mean concentration of choline, cytidine and uridine was 180.88 ± 41.49 μg/mL, 44.45 ± 10.19 μg/mL and 330.41 ± 75.8 μg/mL, respectively. The concentration of citicoline in phakic eyes (n = 13, 366.61 ± 129.61 μg/mL) was lower compared to that found in pseudophakic eyes (n = 8, 435.89 ± 131.42 μg/mL) and the difference was not statistically significant. The concentration of citicoline in the control eyes was 45.66 ± 26.36 μg/mL, while the concentration of choline, cytidine and uridine were 17.21 ± 9.93 μg/mL, 6.24 ± 3.6 μg/mL and 172.80 ± 99.76 μg/mL, respectively. Conclusion Citicoline can reach the human vitreous in high concentration when administered in ophthalmic solution. This evidence contributes to the build-up of the pyramid of the evidences required for determining the role of citicoline administered in ophthalmic formulation in retinal and optic nerve neurodegenerative diseases.

Purpose: To compare the diagnostic accuracy of minimum rim width (MRW), peripapillary retinal nerve fibre layer (pRNFL) and multilayered macular analysis by Spectralis SD-OCT (Heidelberg Engineering, Germany) in discriminating perimetric glaucoma at different stages of the disease from healthy eyes. Methods: In this multicentre, prospective, evaluation of diagnostic tests study, multilayered macular analysis and MRW and pRNFL were obtained from one eye of 197 glaucoma (76 early, 68 moderate and 53 advanced) and of 83 healthy controls from the Multicenter Italian Glaucoma Imaging Study (MIGIS). The reference standard for classifying eyes as glaucomatous and for staging thedisease was the visual field. The main outcome measures were area under the ROC curve (AUC) and sensitivity at fixed specificity (95%). Results: Average MRW and average pRNFL showed the highest and similar diagnostic accuracy in both the whole study population (AUC 0.968 and 0.939) and early glaucoma (AUC 0.956 and 0.929). Among the macular parameters, the three innermost retinal layers combined as the Ganglion Cell Complex provided the highest diagnostic accuracy (AUC 0.931) in the whole population, which was statistically similar to that of average pRNFL but inferior to that of average MRW. Compared to both average MRW and pRNFL, all macular parameters showed statistically significant lower accuracy in early glaucoma, but accuracy in moderate and advanced glaucoma showed no statistically significant differences among three protocols. Conclusion: The diagnostic accuracy of MRW, pRNFL and macular analysis by Spectralis SD-OCT is overall good. MRW and pRNFL analysis performs statistically and clinically better than macular analysis to discriminate early glaucoma from healthy eyes.

Glaucoma is a degenerative disease of the eye. Both the anterior and posterior segments of the eye are affected, extensive damage being detectable in the trabecular meshwork and the inner retina-central visual pathway complex. Oxidative stress is claimed to be mainly responsible for molecular damage in the anterior chamber. Indeed, oxidation harms the trabecular meshwork, leading eventually to endothelial cell decay, tissue malfunction, subclinical inflammation, changes in the extracellular matrix and cytoskeleton, altered motility, reduced outflow facility and (ultimately) increased IOP. Moreover, free radicals are involved in aging and can be produced in the brain (as well as in the eye) as a result of ischemia, leading to oxidation of the surrounding neurons. Glaucoma-related cell death occurs by means of apoptosis, and apoptosis is triggered by oxidative stress via (a) mitochondrial damage, (b) inflammation, (c) endothelial dysregulation and dysfunction, and (d) hypoxia. The proteomics of the aqueous humor is significantly altered in glaucoma as a result of oxidation-induced trabecular damage. Those proteins whose aqueous humor levels are increased in glaucoma are biomarkers of trabecular meshwork impairment. Their diffusion from the anterior to the posterior segment of the eye may be relevant in the cascade of events triggering apoptosis in the inner retinal layers, including the ganglion cells.

The trabecular meshwork (TM) plays an important role in high-tension glaucomas. Indeed, the TM is a true organ, through which the aqueous humor flows from the anterior chamber to Schlemm's canal (SC). Until recently, the TM, which is constituted by endothelial-like cells, was described as a kind of passive filter. In reality, it is much more. The cells delineating the structures of the collagen framework of the TM are endowed with a cytoskeleton, and are thus able to change their shape. These cells also have the ability to secrete the extracellular matrix, which expresses proteins and cytokines, and are capable of phagocytosis and autophagy. The cytoskeleton is attached to the nuclear membrane and can, in millionths of a second, send signals to the nucleus in order to alter the expression of genes in an attempt to adapt to biomechanical insult. Oxidative stress, as happens in aging, has a deleterious effect on the TM, leading eventually to cell decay, tissue malfunction, subclinical inflammation, changes in the extracellular matrix and cytoskeleton, altered motility, reduced outflow facility, and (ultimately) increased IOP. TM failure is the most relevant factor in the cascade of events triggering apoptosis in the inner retinal layers, including ganglion cells. J. Cell. Physiol. 231: 1876-1893, 2016. © 2016 Wiley Periodicals, Inc.

Introduction Primary open angle glaucoma (POAG) is a progressive optic neuropathy characterized by impaired aqueous outflow and extensive remodeling in the trabecular meshwork (TM). The aim of this study was to characterize and compare the expression patterns of selected proteins belonging to the tissue remodeling, inflammation and growth factor pathways in ex vivo glaucomatous and post-mortem TMs using protein-array analysis. Methods TM specimens were collected from 63 white subjects, including 40 patients with glaucoma and 23 controls. Forty POAG TMs were collected at the time of surgery and 23 post-mortem specimens were from non-glaucomatous donor sclerocorneal tissues. Protein profiles were evaluated using a chip-based array consisting of 60 literature-selected antibodies. Results A different expression of some factors was observed in POAG TMs with respect to post-mortem specimens, either in abundance (interleukin [IL]10, IL6, IL5, IL7, IL12, IL3, macrophage inflammatory protein [MIP]1δ/α, vascular endothelial growth factor [VEGF], transforming growth factor beta 1 [TGFβ1], soluble tumor necrosis factor receptor I [sTNFRI]) or in scarcity (IL16, IL18, intercellular adhesion molecule 3 [ICAM3], matrix metalloproteinase-7 [MMP7], tissue inhibitor of metalloproteinase 1 [TIMP1]). MMP2, MMP7, TGFβ1, and VEGF expressions were confirmed by Western blot, zymography, and polymerase chain reaction. No difference in protein profile expression was detected between glaucomatous subtypes. Conclusion The analysis of this small TM population highlighted some proteins linked to POAG, some previously reported and others of new detection (IL7, MIPs, sTNFαRI). A larger POAG population is required to select promising disease-associated biomarker candidates. Funding This study was partially supported by the Fondazione Roma, the Italian Ministry of Health and the “National 5xMille 2010 tax donation to IRCCS-G.B. Bietti Foundation”. Electronic supplementary material The online version of this article (doi:10.1007/s12325-016-0285-x) contains supplementary material, which is available to authorized users.

Background Retinal ganglion cells (RGCs) are the nervous retinal elements which connect the visual receptors to the brain forming the nervous visual system. Functional and/or morphological involvement of RGCs occurs in several ocular and neurological disorders and therefore these cells are targeted in neuroprotective strategies. Cytidine 5-diphosphocholine or Citicoline is an endogenous compound that acts in the biosynthesis of phospholipids of cell membranes and increases neurotransmitters' levels in the Central Nervous System. Experimental studies suggested the neuromodulator effect and the protective role of Citicoline on RGCs. This review aims to present evidence of the effects of Citicoline in experimental models of RGCs degeneration and in human neurodegenerative disorders involving RGCs. Methods All published papers containing experimental or clinical studies about the effects of Citicoline on RGCs morphology and function were reviewed. Results In rodent retinal cultures and animal models, Citicoline induces antiapoptotic effects, increases the dopamine retinal level, and counteracts retinal nerve fibers layer thinning. Human studies in neurodegenerative visual pathologies such as glaucoma or non-arteritic ischemic neuropathy showed a reduction of the RGCs impairment after Citicoline administration. By reducing the RGCs' dysfunction, a better neural conduction along the post-retinal visual pathways with an improvement of the visual field defects was observed. Conclusion Citicoline, with a solid history of experimental and clinical studies, could be considered a very promising molecule for neuroprotective strategies in those pathologies (i.e. Glaucoma) in which morpho-functional changes of RGCc occurs.

The aim of this study was to examine the relationship between visual field (VF) loss, vision-related quality of life (QoL) and glaucoma-related symptoms in a large cohort of primary open angle glaucoma (POAG) patients. POAG patients with or without VF defects or “glaucoma suspect” patients were considered eligible. QoL was assessed using the validated versions of the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) and glaucoma-related symptoms were assessed using the Glaucoma Symptom Scale (GSS). Patients were classified as having VF damage in one eye (VFD-1), both eyes (VFD-2), or neither eye (VFD-0). 3227 patients were enrolled and 2940 were eligible for the analysis. 13.4% of patients were classified in the VFD-0, 23.7% in the VFD-1, and 62.9% in the VFD-2 group. GSS visual symptoms domain (Func-4) and GSS non-visual symptoms domain (Symp-6) scores were similar for the VFD-0 and VFD-1 groups (p = 0.133 and p = 0.834 for Func-4 and Symp-6, respectively). VFD-0 group had higher scores than VFD-2 both in Func-4 (p

Purpose To investigate the serum levels of Brain Derived Neurotrophic Factor (BDNF) and Nerve Growth Factor (NGF) in patients affected by primary open angle glaucoma with a wide spectrum of disease severity compared to healthy controls and to explore their relationship with morphological and functional glaucoma parameters. Materials and Methods 45 patients affected by glaucoma at different stages and 15 age-matched healthy control subjects underwent visual field testing, peripapillary retinal nerve fibre layer thickness measurement using Spectral Domain Optical Coherence Tomography and blood collection for both neurotrophins detection by Enzyme-Linked Immunosorbent Assay. Statistical analysis and association between biostrumental and biochemical data were investigated. Results Serum levels of BDNF in glaucoma patients were significantly lower than those measured in healthy controls (261.2±75.0 pg/ml vs 313.6±79.6 pg/ml, p = 0.03). Subgroups analysis showed that serum levels of BDNF were significantly lower in early (253.8±40.7 pg/ml, p = 0.019) and moderate glaucoma (231.3±54.3 pg/ml, p = 0.04) but not in advanced glaucoma (296.2±103.1 pg/ml, p = 0.06) compared to healthy controls. Serum levels of NGF in glaucoma patients were significantly lower than those measured in the healthy controls (4.1±1 pg/mL vs 5.5±1.2 pg/mL, p = 0.01). Subgroups analysis showed that serum levels of NGF were significantly lower in early (3.5±0.9 pg/mL, p = 0.0008) and moderate glaucoma (3.8±0.7 pg/ml, p

PURPOSE To assess the therapeutic noninferiority of 0.005% latanoprost ophthalmic solution versus Xalatan in the treatment of patients with primary open-angle glaucoma or ocular hypertension. PATIENTS AND METHODS This was a double-masked, randomized, multicenter study. A total of 184 patients with a diagnosis of unilateral or bilateral primary open-angle glaucoma or ocular hypertension were randomly assigned to either 0.005% latanoprost ophthalmic solution or Xalatan for 12 weeks. The primary end-point was the change in intraocular pressure (IOP) at 12 weeks in the 2 groups. Noninferiority was reached if the 2-sided 95% confidence intervals (CI) for the difference between adjusted treatment means were entirely within the interval from -1.5 to +1.5 mm Hg. RESULTS The difference between treatments in the change of IOP from baseline to the end of treatment was 0.12 mm Hg (95% CI: -0.47, 0.71) in the intention-to-treat population and 0 mm Hg (95% CI: -0.58, 0.57) in the per protocol population. There was no statistically significant difference between the 2 groups in terms of drug-related adverse events. The most commonly reported drug-related local adverse events were: ocular hyperemia, eyelashes growth, and eye irritation. CONCLUSIONS This study demonstrates that 0.005% latanoprost ophthalmic solution is noninferior to Xalatan in lowering IOP and is generally well tolerated.

PURPOSE: The purpose of the study was to create a linear discriminant function (LDF) formula by using the new Glaucoma Probability Score (GPS) global and sectorial optic nerve head parameters measured by Heidelberg Retinal Tomograph 3 to improve the GPS diagnostic capacity to discriminate between healthy and glaucomatous eyes. PATIENTS AND METHODS: This is a multicenter cross-sectional study. To calculate the LDF formula, 137 normal individuals and 96 glaucomatous patients were selected. Another independent sample of 60 healthy and 69 glaucomatous eyes was used to evaluate the diagnostic accuracy of the LDF formulas. All patients underwent a full eye examination, standard achromatic perimetry by using Humphrey Field Analyzer, and imaging with Heidelberg Retinal Tomograph 3. Glaucoma was defined on the basis of SITA-24-2 visual field loss (pattern standard deviation P

Background Spectral-domain optical coherence tomography (SD-OCT) provides fast scan speed and high scan resolution improving its diagnostic accuracy. The purpose of this study was to evaluate if SD-OCT measurements and their quality score are influenced by pupil dilation. Methods Retinal nerve fiber layer thickness (RNFL), ganglion cell complex (GCC) and optic nerve head (ONH) were measured in one eye of 57 glaucoma patients and 36 healthy subjects using spectral domain optical coherence tomography (SD-OCT) before and after pupil dilation. Comparisons were made between measurements and their quality score pre- and post dilation (Signal Strength Index, SSI). Overall RNFL, average GCC and ONH rim volume were considered in the analysis. Results No statistically significant differences were found between pre- and post-dilation measurements in both groups (glaucoma: RNFL 80 ± 15 μm vs 80 ± 16 μm, p = 0.87; GCC 81.35 ± 13.4 μm vs 81.10 ± 13.14 μm, p = 0.92; ONH 0.05 ± 0.11 mm3 vs 0.04 ± 0.07 mm3, p = 0.74; controls RNFL 99 ± 12 μm vs 98 ± 14 μm, p = 0.70; GCC 92.12 ± 6.7 μm vs 91.54 ± 7.05 μm, p = 0.72; ONH 0.11 ± 0.1 mm3 vs 0.04 ± 0.07 mm3, p = 0.36) nor between pre- and post-dilation quality score (glaucoma SSI RNFL 54.3 ± 10.3 vs 51.7 ± 18.1, p = 0.12; SSI GCC 58 ± 9.5 vs 57 ± 8.09, p = 0.55; SSI ONH 48.5 ± 7.6 vs 46.6 ± 7.2, p = 0.16; controls SSI RNFL 57 ± 10.3 vs 54 ± 9.31, p = 0.2; SSI GCC 60.9 ± 8.1 vs 58.8 ± 7.3, p = 0.3; SSI ONH 51.5 ± 8.9 vs 50.4 ± 8.3, p = 0.59). Conclusion Pupil dilation doesn’t affect SD-OCT measurements and their quality score.

Aim: To evaluate the learning effect of Frequency Doubling Technology (FDT) perimetry using the Humphrey Matrix-FDT perimetry (Matrix) 24-2 full-threshold program on patients with 7 ocular hypertension experienced with standard automated perimetry. Methods: Twenty-four patients with Ocular hypertension underwent 5 full-threshold Matrix tests at intervals of 5 2 days. Learning effect was defined as an improvement at results for duration, perimetric indices, foveal sensitivity, Glaucoma Hemifield Test, and the number of points with a P < 5% and < 1% in the total and pattern deviation maps. Eccentricity, hemifield, and quadrant sensitivities were also addressed as Sources of differences in learning effect. Test-retest variability was also calculated for each repetition as the mean of the point-to-point interindividual standard deviations. Results: A learning effect was demonstrated for mean defect (P = 0.031, analysis of variance) and foveal sensitivity (P = 0.009) and it only affected the first test for both parameters. All the other parameters did not show any significant learning effect. The effect was independent From eccentricity and quadrant or hemifield sensitivities. Conclusions: The results of this study demonstrate that the learning effect for Matrix-FDT is mild and it may affect only the first test. Caution is needed in the analysis of the first Matrix-FDT examination and retest may be advisable in the presence of low mean defect.

To evaluate the retinal function and the neural conduction along the visual pathways after treatment with citicoline eye drops in patients with open angle glaucoma (OAG).Fifty-six OAG patients (mean age 52.4 ± 4.72 years, IOP18 mmHg with beta-blocker monotherapy only) were enrolled. Of these, 47 eyes completed the study: 24 OAG eyes were treated with topical citicoline (OMK1®, Omikron Italia, 3 drops/day) (GC eyes) over a 4-month period (month 4) followed by a 2-month period of citicoline wash-out (month 6), and another 23 OAG eyes were only treated with beta-blocker monotherapy (GP eyes). In GC and GP eyes, pattern electroretinogram (PERG) and visual evoked potentials (VEP) were assessed at baseline and at months 4 and 6 in both groups.At baseline, similar (ANOVA, p 0.01) PERG and VEP values in GC and GP eyes were observed. After treatment with topical citicoline, a significant (p 0.01) increase of PERG P50-N95 and VEP N75-P100 amplitudes, and a significant (p 0.01) shortening of VEP P100 implicit times were found. In GC eyes, the shortening of VEP P100 implicit times was correlated significantly (p 0.01) with the increase of PERG P50-N95 amplitudes. After a 2-month period of topical Citicoline wash-out, PERG and VEP values were similar (p 0.01) to baseline ones. GP eyes showed not significant changes of PERG and VEP values during the entire follow-up.Topical treatment with citicoline in OAG eyes induces an enhancement of the retinal bioelectrical responses (increase of PERG amplitude) with a consequent improvement of the bioelectrical activity of the visual cortex (shortening and increase of VEP implicit time and amplitude, respectively).

Purpose To compare the 24-hour (24h) effects on intraocular pressure (IOP) and cardiovascular parameters of timolol 0.5% and bimatoprost 0.01% in open angle glaucoma and ocular hypertensive subjects. Methods In this prospective, randomized, double masked, crossover, clinical trial, after washout from previous medications enrolled subjects underwent 24h IOP, blood pressure (BP) and heart rate (HR) measurements and were randomized to either topical bimatoprost 0.01% at night plus placebo in the morning or to timolol 0.5% bid. After 8 weeks of treatment a second 24h assessment of IOP, BP and HR was performed and then subjects switched to the opposite treatment for additional 8 weeks when a third 24h assessment was performed. The primary endpoint was the comparison of the mean 24h IOP after each treatment. Secondary endpoints included the comparisons of IOP at each timepoint of the 24h curve and the comparison of BP, HR, ocular perfusion pressure and tolerability. Results Mean untreated 24h IOP was 20.3 mmHg (95%CI 19.0 to 21.6). Mean 24h IOP was significantly lower after 8 weeks of treatment with bimatoprost 0.01% than after 8 weeks of treatment with timolol 0.5% bid (15.7 vs 16.8 mmHg, p = 0.0003). Mean IOP during the day hours was significantly reduced from baseline by both drugs while mean IOP during the night hours was reduced by -2.3 mmHg (p = 0.0002) by bimatoprost 0.01% plus placebo and by -1.1 mmHg by timolol 0.5% bid (p = 0.06). Timolol 0.5% significantly reduced the mean 24h systolic BP from baseline, the diastolic BP during the day hours, the HR during the night hours, and the mean 24h systolic ocular perfusion pressure. Conclusion Both Bimatoprost 0.01% and Timolol 0.5% are effective in reducing the mean 24h IOP from an untreated baseline but Bimatoprost 0.01% is more effective than timolol 0.5% throughout the 24h. Timolol 0.5% effect on IOP is reduced during the night hours and is associated with reduced BP, HR and ocular perfusion pressure. Trial Registration EU Clinical Trial Register and EudraCT# 2010-024272-26

BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder, which is likely to start as mild cognitive impairment (MCI) several years before the its full-blown clinical manifestation. Optical coherence tomography (OCT) has been used to detect a loss in peripapillary retina nerve fiber layer (RNFL) and a reduction in macular thickness and volume of people affected by MCI or AD. Here, we performed an aggregate meta-analysis combining results from different studies.Methods and findingsData sources were case-control studies published between January 2001 and August 2014 (identified through PubMed and Google Scholar databases) that examined the RNFL thickness by means of OCT in AD and MCI patients compared with cognitively healthy controls.Results11 studies were identified, including 380 patients with AD, 68 with MCI and 293 healthy controls (HC). The studies suggest that the mean RNFL thickness is reduced in MCI (weighted mean differences in μm, WMD = -13.39, 95% CI: -17.34 to -9.45, p = 0.031) and, even more so, in AD (WMD = -15.95, 95% CI: -21.65 to -10.21, p

To determine the proportion of patients with primary open-angle glaucoma (POAG) or ocular hypertension (OH) who do not respond to latanoprost therapy.Three hundred forty consecutive patients with a new diagnosis of POAG or OH, or previously treated only with a beta-blocker and after an appropriate washout period, were treated with latanoprost for 1 month and then divided into three groups on the basis of the reduction in intraocular pressure (IOP): nonresponders (15%), responders (or =15% but30%), and high-responders (or =30%). To give a wide picture of the drug effect, eight different cut-off points were used to present data on distribution of mean IOP reductions. Only the nonresponders entered a randomized cross-over study investigating the efficacy of timolol, brimonidine, and pilocarpine.IOP at baseline and after 1 month's latanoprost therapy was respectively 24.1+/-1.4 and 16.9+/-2.4 mm Hg, with a mean reduction in IOP of 29.9+/-4.2%. Nonresponders accounted for 4.1% of the patients and high-responders for 41.2%. The nonresponders showed a statistically significant reduction in IOP after brimonidine treatment (P=0.05), whereas the reduction after timolol and pilocarpine treatment was clinically relevant but not statistically significant.This multicenter prospective study found only 14 of 340 nonresponders to latanoprost. In the cross-over trial on nonresponders, IOP reduction reached statistical significance only after brimonidine, but their small number reduced its statistical power.

Purpose To evaluate the ocular surface inflammatory response to the presence of preservatives in nonselective beta-blocker eyedrops. Design Prospective, crossover, single-masked, randomized clinical study. Methods study population: Twenty primary open-angle glaucoma or ocular hypertensive patients were divided in two groups, one treated with preservative-free timolol 0.5% (group 1) and the other with preserved timolol 0.5% (group 2) eyedrops. After 60 days of therapy and 3 more weeks of washout, the two groups switched to the other therapy. procedure: At each visit, basal tear samples were collected from the inferior conjunctival fornix for the determination of interleukin (IL)-1β tear concentrations by an enzyme-linked immunosorbent assay. Intraocular pressure measurement, conjunctival hyperemia, superficial punctate keratitis, and tear film breakup time were evaluated. main outcome measure: IL-1β concentration in tears following the use of preserved eyedrops. Results IL-1β tear concentrations increased significantly in both groups, compared with baseline values, during preserved timolol therapy. There were no statistically significant changes in hyperemia and superficial punctate keratitis throughout the study in either group. A statistically significant breakup time reduction was observed in both groups after 30 days and after 60 days of preserved therapy. Conclusion The use of preservatives in timolol 0.5% eyedrops leads to tear film instability and ocular surface inflammatory changes documented by a reduction of breakup time and an increase of IL-1β tear concentrations. Preservative-free beta-blockers are preferable for long-term hypotensive therapy to prevent ocular surface inflammation.

[corrected] To correlate the nerve fiber layer (NFL) thickness and the visual function evaluated by electrophysiologic retinal and cortical responses assessed in open-angle glaucoma (OAG) eyes.Prospective case-control study.Thirty glaucoma patients (mean age, 47.1 +/- 7.15 years; refractive error range, +/- 2 spherical equivalent) with a mean deviation of computerized static perimetry (24/2 Humphrey, Dublin, CA) from -5 to -28 dB and intraocular pressure less than 21 mmHg on pharmacologic treatment and 14 age-matched control participants.Nerve fiber layer thickness was measured by optical coherence tomography. Retinal and visual pathway function was assessed by simultaneously recording pattern electroretinograms (PERGs) and visual evoked potentials (VEPs) using high-contrast (80%) checkerboard stimuli (the single check edges subtend 15 minutes of the visual arc) reversed at the rate of two reversals per second. Linear regression analyses were adopted to establish the correlation between NFL thickness and PERG and VEP parameters.Nerve fiber layer thickness measurements in each quadrant (superior, inferior, nasal, and temporal) were taken and then averaged (12 values averaged) and identified as NFL overall, whereas the data obtained in the temporal quadrant only (three values averaged) were identified as NFL temporal. PERG P50 implicit time and P50-N95 amplitude and VEP P100 implicit time and N75-P100 amplitude were also measured.In OAG eyes, we found a significant (P0.01) reduction in NFL thickness in both NFL overall and NFL temporal evaluations with respect to the values observed in control eyes. PERG and VEP parameters showed a significant (P0.01) delay in implicit time and a reduction in peak-to-peak amplitude. In OAG eyes, the NFL overall and NFL temporal values were significantly correlated (P0.01) with the PERG P50 implicit time and P50-95 peak-to-peak amplitude. No correlations (P0.01) between NFL values and VEP parameters were found.There is a correlation between PERG changes and NFL thickness, but there is no correlation between VEP changes and NFL thickness in patients affected by OAG.

Purpose To evaluate the effects of cytidine-5′-diphosphocholine (citicoline) on retinal function and on cortical responses in patients with glaucoma. Design Randomized clinical trial. Participants Forty patients with open-angle glaucoma were randomly divided into two age-matched groups: citicoline group ([GC] n=25) and placebo group ([GP] n=15). Methods The GC patients were treated with Neuroton (citicoline, 1000 mg/day intramuscularly) for 60 days; GP patients were treated with placebo (physiologic solution with additives) for 60 days. After 120 days of washout (day 180), the GC patients were divided into two age-matched groups: in 10 patients (GC1 group) the washout was prolonged for a further 120 days; in 15 patients (GC2 group) a second 60-day period of citicoline treatment was followed by a second 120-day period of washout. At day 180, the washout was extended for another 180 days in GP patients. In all subjects, retinal and cortical responses were evaluated by simultaneous recordings of visual evoked potentials (VEPs) and pattern-electroretinograms (PERGs) at baseline, after 60 days, and after 180 days. At day 300, VEPs and PERGs were also evaluated in GC1 patients, and at 240 and 360 days in GC2 and GP patients. Main outcome measures Visual evoked potential parameters (P100 latency and N75-P100 amplitude); PERG parameters (P50 latency and P50-N95 amplitude); and intraocular pressure. Results The GP patients displayed similar VEP and PERG parameters in all examinations performed. In GC patients, the treatment with citicoline induced a significant ( P P P P > 0.05) to baseline ones and to those of GP patients. In GC2 patients, a second period of citicoline treatment induced a further ( P Conclusion Citicoline may induce an improvement of the retinal and of the visual pathway function in patients with glaucoma.

Purpose: To assess the effect of citicoline on visual field rates of progression in patients with progressing glaucoma. Patients and Methods: Forty-one patients with a diagnosis of progressing glaucoma received citicoline in oral solution for 2 years. Included were patients with a disease progression of at least -1 dB/year (at MD, mean deviation) for at least 3 years before entering the study despite controlled intraocular pressure (IOP). Patients were followed with 4 visual field examinations per year for 2 years. Results: At baseline, the mean rate of progression was -1.1 (±0.7) dB/year despite the fact that the IOP had been below 18 mm Hg for at least 3 years. At study inclusion, the mean IOP was 15.5 (±2.6) mm Hg and the mean MD was -9.2 (±6.7) dB in the worst eye. Starting from the first cycle of treatment with citicoline, the mean rate of progression significantly changed to -0.15 (±0.3) dB/year at the end of the study (p = 0.01). Conclusions: This study seems to indicate that supplementation with citicoline might significantly slow down glaucomatous rates of progression.

Aims: To evaluate short- (ST) and long-term (LT) intraocular pressure (IOP) in patients with stable (SG) and progressive glaucoma (PG). Materials and Methods: Fifty-two patients with treated glaucoma received a baseline 24-hour IOP curve and, every 6 months for 2 years, office-hour curve plus visual field test. Based on field changes, they were divided into 24 SG and 28 PG. ST and LT IOP mean, peak and fluctuation (standard deviation of measurements) were calculated. Parameters determining progression were evaluated by logistic regression. Results: At ST, SG and PG, respectively, had mean IOP of 16.8 ± 2.2 and 15.3 ± 1.8 mm Hg; peak of 19.7 ± 3.3, 17.4 ± 2.3 mm Hg; fluctuation of 2.3 ± 1.2, and 1.6 ± 0.6 mm Hg. LT parameters did not change in SG, whereas a significant increase of mean (+1.0 ± 1.5 mm Hg, p = 0.05), peak (2.0 ± 2.4 mm Hg, p = 0.0002), and fluctuation (0.5 ± 1.1 mm Hg, p = 0.008) occurred in PG. Mean, peak, and fluctuation were correlated, except mean and fluctuation in the long term. Association with progression was shown for change in mean IOP between ST and LT, and ST peak. Conclusions: SG and PG may show different IOP parameters when intensively measured at baseline and follow-up. Mean IOP change between ST and LT periods and ST peak were the parameters associated with progression.

Aim To examine the level of agreement among nine clinicians in assessing progressive deterioration in visual field (VF) overview using three different methods of analysis. Methods Each visual field was assessed by Humphrey Field Analyzer (HFA), program 24-2 SITA Standard. Nine expert clinicians assessed the progression status of each series by using HFA ‘overview printouts’ (HFA OP), the Guided Progression Analysis (GPA) and the Guided Progression Analysis (GPA2). VF series were presented in random order, but each patient9s VF remained in chronological order within a given field series. Each clinician adopted his personal methods based on his knowledge to evaluate VF progression. The level of agreement between the clinicians was evaluated by using weighted κ statistics. Results A total of 303 tests, comprising 38 visual field series of 7.9±3.4 tests (mean±SD), were assessed by the nine glaucoma specialists. When the intra-observer agreement was evaluated between HFA OP and GPA, the mean κ statistic was 0.58±0.13, between HFA OP and GPA2, κ was 0.55±0.06 and between GPA and GPA2 it was 0.56±0.17. When the inter-observer agreement was analysed κ statistic was 0.65 for HFA OP, 0.54 for GPA and 0.70 for GPA2. Conclusions Using any procedure for evaluating the progression of a series of VF, agreement between expert clinicians is moderate. Clinicians had higher agreement when GPA2 was used, followed by HFA OP and GPA printouts, but these differences were not significant.