Glaucoma, Pseudoexfoliation and Hearing Loss: A Systematic Literature Review.

Purpose: To investigate the relationship between glaucoma, pseudoexfoliation and hearing loss (HL). Methods: A systematic literature search following PRISMA guidelines was conducted using the PubMed, Embase, Scopus and Cochrane databases from 1995 up to 28 August 2023. Results: Thirty studies out of the 520 records screened met the inclusion criteria and were included. Most articles (n = 20) analysed the association between pseudoexfoliation syndrome (XFS) and HL, showing XFS patients to have higher prevalence of sensorineural hearing loss (SNHL) at both speech frequencies (0.25, 0.5, 1 and 2 kHz), and higher frequencies (4 and 8 kHz) compared to controls in most cases. No significant differences in prevalence or level of HL between XFS and pseudoexfoliative glaucoma (XFG) were detected in most studies. Eight articles analysed the relationship between primary open-angle glaucoma (POAG) and HL. Overall, a positive association between the two conditions was highlighted across all studies except for two cases. Similarly, articles focusing on NTG and HL (n = 4) showed a positive association in most cases. The role of autoimmunity and, in particular, the presence of antiphosphatidylserine antibodies (APSA) in patients with NTG and HL suggested an underlying autoimmune or vascular mechanism contributing to their pathogenesis. Only one study analysed the relationship between angle-closure glaucoma (ACG) and HL, showing higher incidence of ACG in patients with SNHL compared to normal hearing controls. Conclusions: Most studies detected an association between XFS and HL as well as POAG/NTG/ACG and HL, suggesting the presence of a similar pathophysiology of neurodegeneration. However, given the strength of the association of XFS with HL, it remains unclear whether the presence of XFG is further associated with SNHL. Further research specifically targeted to assess the correlation between glaucoma, XFS and HL is warranted to provide a more comprehensive understanding of this association.

Ubiquitin proteasome system and glaucoma: A survey of genetics and molecular biology studies supporting a link with pathogenic and therapeutic relevance.

Glaucoma represents a group of progressive neurodegenerative diseases characterized by the loss of retinal ganglion cells (RGCs) and their axons with subsequent visual field impairment. The disease develops through largely uncharacterized molecular mechanisms, that are likely to occur in different localized cell types, either in the anterior (e.g., trabecular meshwork cells) or posterior (e.g., Muller glia, retinal ganglion cells) segments of the eye. Genomic and preclinical studies suggest that glaucoma pathogenesis may develop through altered ubiquitin (Ub) signaling. Ubiquitin conjugation, referred to as ubiquitylation, is a major post-synthetic modification catalyzed by E1-E2-E3 enzymes, that profoundly regulates the turnover, trafficking and biological activity of the targeted protein. The development of new technologies, including proteomics workflows, allows the biology of ubiquitin signaling to be described in health and disease. This post-translational modification is emerging as a key role player in neurodegeneration, gaining relevance for novel therapeutic options, such as in the case of Proteolysis Targeting Chimeras technology. Although scientific evidence supports a link between Ub and glaucoma, their relationship is still not well-understood. Therefore, this review provides a detailed research-oriented discussion on current evidence of Ub signaling in glaucoma. A review of genomic and genetic data is provided followed by an in-depth discussion of experimental data on ASB10, parkin and optineurin, which are proteins that play a key role in Ub signaling and have been associated with glaucoma.

Novel frontiers in neuroprotective therapies in glaucoma: Molecular and clinical aspects.

In the last years, neuroprotective therapies have attracted the researcher interests as modern and challenging approach for the treatment of neurodegenerative diseases, aimed at protecting the nervous system from injuries. Glaucoma is a neurodegenerative disease characterized by progressive excavation of the optic nerve head, retinal axonal injury and corresponding vision loss that affects millions of people on a global scale. The molecular basis of the pathology is largely uncharacterized yet, and the therapeutic approaches available do not change the natural course of the disease. Therefore, in accordance with the therapeutic regimens proposed for other neurodegenerative diseases, a modern strategy to treat glaucoma includes prescription of drugs with neuroprotective activities. With respect to this, several preclinical and clinical investigations on a plethora of different drugs are currently ongoing. In this review, first, the conceptualization of the rationale for the adoption of neuroprotective strategies for retina is summarized. Second, the molecular aspects highlighting glaucoma as a neurodegenerative disease are reported. In conclusion, the molecular and pharmacological properties of most promising direct neuroprotective drugs used to delay glaucoma progression are examined, including: neurotrophic factors, NMDA receptor antagonists, the α2-adrenergic agonist, brimonidine, calcium channel blockers, antioxidant agents, nicotinamide and statins.

The effect of citicoline oral solution on quality of life in patients with glaucoma: the results of an international, multicenter, randomized, placebo-controlled cross-over trial.

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.

Efficacy of Nonpreserved Sodium Hyaluronate Artificial Tears in Dry Eye Disease Patients Treated with Prostaglandin Analogs for Primary Open-Angle Glaucoma: A Prospective, Nonrandomized, Open-Label Pilot Study.

Purpose: Dry eye disease (DED) can be triggered using preserved ophthalmic formulations or prostaglandin analogs. In this prospective, nonrandomized, open-label pilot study, we evaluated the efficacy of a 0.15% hyaluronic acid (HA) nonpreserved ophthalmic formulation in decreasing DED symptoms in patients with open-angle glaucoma treated with prostaglandin analogs. Methods: 30 patients with DED receiving chronic treatment with prostaglandin analogs for primary open-angle glaucoma or ocular hypertension were administered ophthalmic formulations 3 times daily for 12 weeks. Foreign body sensation, burning, stinging, dryness, pain, frequency of symptoms, Ocular Surface Disease Index (OSDI), conjunctival hyperaemia, corneal fluorescein staining (CFS), tear film break-up time (TBUT), best-corrected visual acuity, Schirmer test results, and 25-item National Eye Institute Visual Function Questionnaire score between the baseline and 4 and 12 weeks were evaluated. Results: The analysis shows that all primary endpoints improved; in particular, burning sensation and the frequency of symptoms after 4 and 12 weeks of treatment (p < 0.001) and dryness and pain after 12 weeks of treatment (p < 0.001 and p=0.03, respectively) were reduced significantly. Secondary outcomes confirmed the positive results, with a statistically significant change in the OSDI score and CFS between the baseline and 4 (p=0.02 and p < 0.001, respectively) or 12 weeks (both p < 0.001) and TBUT after 4 weeks (p=0.01). Conjunctival hyperaemia improved in both eyes in >90% of cases at 12 weeks of treatment. Conclusion: The present study shows that the ophthalmic formulation containing 0.15% HA has a promising beneficial effect on reducing the signs and symptoms of DED in patients treated with prostaglandin analogs.

Neural Conduction Along Postretinal Visual Pathways in Glaucoma.

Purpose: This study was conducted in order to evaluate retinal ganglion cell (RCG) function and the neural conduction along the postretinal large and small axons and its correlation with retinal nerve fiber layer thickness (RNFL-T) in open-angle glaucoma (OAG) eyes. Methods: Thirty-seven OAG patients (mean age: 51.68 ± 9.83 years) with 24-2 Humphrey mean deviation (MD) between -2.5 and -20 dB and IOP <21 mmHg on pharmacological treatment (OAG group) and 20 age-matched controls (control group) were enrolled. In both groups, simultaneous pattern electroretinograms (PERG) and visual evoked potentials (VEP), in response to checks stimulating macular or extramacular areas (the check edge subtended 15' and 60' of visual arc, respectively), and RNFL-T (measured in superior, inferior, nasal, and temporal quadrants) were assessed. Results: In the OAG group, a significant (ANOVA, p < 0.01) reduction of 60' and 15' PERG P50-N95 and VEP N75-P100 amplitudes and of RNFL-T [overall (average of all quadrants) or temporal] with respect to controls was found; the values of 60' and 15' PERG P50 and VEP P100 implicit times and of retinocortical time (RCT; difference between VEP P100 and PERG P50 implicit times) were significantly (p < 0.01) increased with respect to control ones. The observed increased RCTs were significantly linearly correlated (Pearson's test, p < 0.01) with the reduced PERG amplitude and MD values, whereas no significant linear correlation (p < 0.01) with RNFL-T (overall or temporal) values was detected. Conclusions: In OAG, there is an impaired postretinal neural conduction along both large and small axons (increased 60' and 15' RCTs) that is related to RGC dysfunction, but independent from the RNFL morphology. This implies that, in OAG, the impairment of postretinal neural structures can be electrophysiologically identified and may contribute to the visual field defects, as suggested by the linear correlation between the increase of RCT and MD reduction.

Confocal Microscopy and Anterior Segment Optical Coherence Tomography Imaging of the Ocular Surface and Bleb Morphology in Medically and Surgically Treated Glaucoma Patients: A Review.

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.

Dexamethasone Downregulates Autophagy through Accelerated Turn-Over of the Ulk-1 Complex in a Trabecular Meshwork Cells Strain: Insights on Steroid-Induced Glaucoma Pathogenesis.

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).

Citicoline in Ophthalmological Neurodegenerative Disease: A Comprehensive Review.

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).

Common aspects between glaucoma and brain neurodegeneration.

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.

Can Treatment With Citicoline Eyedrops Reduce Progression in Glaucoma? The Results of a Randomized Placebo-controlled Clinical Trial.

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.

Structural and functional evidence for citicoline binding and modulation of 20S proteasome activity: Novel insights into its pro-proteostatic effect.

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.

Steroid-induced glaucoma: Epidemiology, pathophysiology, and clinical management.

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.

Exploring the gap between diagnostic research outputs and clinical use of OCT for diagnosing glaucoma.

AIMS: To 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. METHODS: Consecutive 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. RESULTS: 280 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. CONCLUSIONS: The 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.

Human vitreous concentrations of citicoline following topical application of citicoline 2% ophthalmic solution.

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.

Tear Film, Conjunctival and Corneal Modifications Induced by Glaucoma Treatment.

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.

Enhancement of Retinal Function and of Neural Conduction Along the Visual Pathway Induced by Treatment with Citicoline Eye Drops in Liposomal Formulation in Open Angle Glaucoma: A Pilot Electrofunctional Study.

INTRODUCTION: 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). METHODS: Twelve OAG patients (mean age ± standard deviation 52.58 ± 11.39 years, intraocular pressure < 18 mmHg under topical hypotensive treatment, Humphrey field analyzer mean deviation - 4.49 ± 2.46 dB) were enrolled. Only one eye of studied patients was treated with CLF eye drops (OMK1-LF®, Omikron Italia, 3 drops/day) (CLF group, 12 eyes) over a period of 4 months. In CLF eyes, pattern electroretinogram (PERG), visual evoked potentials (VEP), and visual field test were assessed at baseline and at the end of treatment (month 4). RESULTS: After treatment with CLF eye drops, a significant increase of PERG P50-N95 amplitude and a significant shortening of VEP P100 implicit time were found. In CLF eyes, the shortening of VEP P100 implicit time was significantly correlated with the increase of PERG P50-N95 amplitude. CONCLUSION: Data from this pilot study suggest that treatment with CLF eye drops 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 of VEP implicit time). FUNDING: Omikron Italia S.r.l. and Opko Health Europe.

Macular versus nerve fibre layer versus optic nerve head imaging for diagnosing glaucoma at different stages of the disease: Multicenter Italian Glaucoma Imaging Study.

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 the disease 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.

Prospective, Randomized, Single Masked, Parallel Study Exploring the Effects of a Preservative-Free Ophthalmic Solution Containing Hyaluronic Acid 0.4% and Taurine 0.5% on the Ocular Surface of Glaucoma Patients Under Multiple Long-Term Topical Hypotensive Therapy.

INTRODUCTION: To compare the effects of a preservative-free (PF) ophthalmic solution containing hyaluronic acid (HA) 0.4% and taurine (TAU) 0.5% with those of a PF ophthalmic solution containing HA 0.2% on ocular surface signs, symptoms, and morphological parameters in glaucoma patients under multiple long-term topical hypotensive therapy. METHODS: Eligible patients underwent evaluation of ocular surface parameters by ocular surface disease index (OSDI) and glaucoma symptom scale (GSS) questionnaires, breakup time test (BUT), Schirmer I test, corneal and conjunctival staining (Oxford scale), and conjunctival in vivo confocal microscopy (Heidelberg Retina Tomograph 3, Heidelberg Engineering GmbH, Heidelberg, Germany). After the baseline visit, patients were randomized to use a PF ophthalmic solution containing HA 0.4% and TAU 0.5%, QID, in both eyes (group 1) or to use a PF ophthalmic solution containing HA 0.2%, QID (group 2) in addition to the ongoing preserved hypotensive treatment. Follow-up visits were scheduled at 30 and 90 days. RESULTS: Thirty-nine eyes of 39 glaucoma patients were included in the study. At baseline, results of study tests of both groups were similar. After 90 days in group 1 the BUT (p = 0.01), the Oxford score (p = 0.03), the conjunctival goblet cells (CGC) density (p = 0.0005) ,and the two questionnaires score significantly improved (OSDI, p = 0.003; GSS, p = 0.003) compared to baseline values, while in group 2 all these parameters did not differ from baseline (BUT, p = 0.39; Oxford score, p = 0.54; CGC density, p = 0.33, OSDI p = 0.65, GSS, p = 0.25). The BUT and the CGC density were statistically different between groups both at 30 and 90 days (p = 0.04 and p = 0.04, respectively). The Schirmer I test did not statistically change after 90 days in both groups. CONCLUSIONS: The PF ophthalmic solution with HA 0.4% and TAU 0.5% seems to improve CGC density and reduce signs and symptoms of dry eye in glaucoma patients under long-term multiple preserved hypotensive therapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03480295.

Citicoline and Retinal Ganglion Cells: Effects on Morphology and Function.

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.