Glaucoma is a progressive optic neuropathy and its main treatment consists of reducing the intraocular pressure. Alongside this therapy, over the years, other substances with direct neuroprotective action have been studied, identified on the basis of the new molecular targets implicated in the etiopathogenesis of the disease. This review illustrates the current evidence regarding the therapeutic targets of the various substances proposed and studied from an experimental and clinical point of view. The most recent evidences regarding new therapeutic approaches, as well as some aspects of alternative and behavioral medicine are also reported. The aim of this review is to be comprehensive but friendly and to transfer, as far as possible, the data provided by the research into current clinical practice.

Purpose: The aim of the study was to evaluate the presence of alterations in the tear film osmolarity and in other parameters that can define the OSD in POAG/OH patients treated with different topical therapies in order to better define the role of osmolarimetry in the clinical management of patients in a real life setting. Methods: This is a cross-sectional, observational study. All patients with POAG/OH treated with topical medications and 20 subjects age and sex matched as a control group, were consecutively and prospectively enrolled. The following exams were performed: tear film osmolarity assessed using Tearlab®, tear break-up time (TBUT), corneal staining score (Oxford scale), ocular symptom assessment using Ocular Surface Disease Index (OSDI) questionnaire. These data were compared between POAG/OH patients and control group and correlations were analysed between tear film osmolarity and other DED parameters. Results: 50 POAG/OH patients (25 M/25F; mean age 69 ± 17y) and 20 controls, matched for age and sex, were enrolled. The mean treatment duration was 2.5 ± 1.2 years. Benzalkonium chloride (BAK) was used in 92% of cases. The mean osmolarity value (mOsms/L) in POAG/OH patients was 306 ± 12 versus 296 ± 12 in control group ( p < 0.05). TBUT (sec) was 5 ± 2 versus 9 ± 2 ( p < 0.05). OSDI ranged from 0 to 96 and the mean value was 18 ± 19 in the study group vs 16 ± 14 in controls (NS). No significant difference was found in corneal staining between the two groups. In POAG/OH eyes tear film osmolarity values were ≤308 in 17/50 (34%) patients and in control group were 4/20 (20%). TBUT<8 s in 41/50(82%) vs 5/20 (25%). OSDI was <12 in 50% of cases vs 55% of controls, ranging from 13 to 32 in 36% versus 30% and from 33 to 100 in 14% versus 20%; corneal staining >1 in 12% versus 10%. Tear osmolarity was significantly correlated to TBUT ( r = 0.11; p = 0.05). Conclusions: The differences between OSM and TBUT are statistically significant between the two groups. OSDI score difference is not significant, but the self-administered questionnaire has inherent limitations. Tear film osmolarimetry has the advantage of providing a quantitative, operator-independent indication of possible ocular surface dysfunction and it may be useful in the real life practice of a glaucoma unit in identifying the most vulnerable patients who might benefit from a switch to BAK-free preparations.

Purpose To evaluate the potential beneficial and synergistic effects of oral intake of a fixed combination of citicoline 500 mg plus homotaurine 50 mg (CIT/HOMO) on retinal ganglion cell (RGC) function in subjects with glaucoma using pattern electroretinogram (PERG) and to investigate the effects on visual field and quality of life. Methods Consecutive patients with primary open-angle glaucoma with controlled IOP (<18 mmHg) receiving beta-blockers and prostaglandin analogs alone or as combination therapy (fixed or un-fixed); with stable disease (progression no more than −1 dB/year at the visual field MD); and an early to moderate visual field defect (MD < −12 dB) were randomized to: arm A. topical therapy + CIT/HOMO for 4 months, 2 months of wash out, 4 months of topical therapy alone; arm B. topical therapy alone for 4 months, topical therapy + CIT/HOMO for 4 months, 2 months of wash out. All patients underwent 4 visits: complete ocular examination, visual field, PERG and quality of life assessment (NEI-VFQ25) were performed at each visit. Results Fifty-seven patients completed the study: 26 in group A and 31 in group B. At the end of the intake period, PERG's P50 and N95 waves recorded a greater amplitude. The increase was statistically significant in the inferior and superior P50 waves amplitude: 0.47 μV (95%CI, 0.02–0.93; p = 0.04) and 0.65 μV (95% CI, 0.16–1.13; p = 0.009), respectively, and in the inferior N95 wave amplitude 0.63 μV (95% CI, 0.22–1.04; p = 0.002). A significantly shorter peak time of 3.3 μV (95% CI, −6.01– −0.54; p = 0.01) was observed for the superior P50 wave only. Conclusions Daily oral intake of the fixed combination CIT/HOMO for 4 months improved the function of inner retinal cells recorded by PERG in the inferior and in the superior quadrants, independently from IOP reduction. This interesting association could represent a valid option for practicing neuromodulation in patients with glaucoma to prevent disease progression.

Purpose Systemic retinoids are among the most prescribed drugs in dermatology, thanks to their activity as proliferation modulators and keratinisation normalisers. Common side effects such as blood lipid disorders, xerosis and photosensitivity are well established and usually dose dependent. Conversely, retinoid-associated ocular disturbances have been reported, yet with differences in terms of frequency and manifestations As data regarding a potential correlation with refractive errors are heterogenous and have not been previously thoroughly addressed, we performed a systematic review of the literature with the aim of comprehensively evaluating the current evidence regarding retinoid-associated myopia in dermatologic patients. Materials and Methods A systematic review of the literature was carried out according to the PRISMA guidelines . A search on MEDLINE, Pubmed, Scopus, Cochrane Library was conducted using the MeSH terms: retinoid, isotretinoin, acitretin, bexarotene, etretinate, alitretinoin, myopia, refractive errors, via the Boolean term AND. Only manuscripts in English were considered, there was no restriction on type of article . Animal research and in vitro studies were excluded. Results Six articles were finally included in this systematic review. One well designed prospective study was able to show a slight myopic shift in the first six months , but id did not evaluate further development of the refractive error nor the effects of drug discontinuation. Another prospective study, with a smaller sample size showed no myopic progression at 12 months. Two case reports showed a myopic shift after two weeks from therapy start . Another case report showed a myopic shift associated with narrowing of the anterior chamber after one week from therapy start. Finally a large retrospective study based on spontaneous reporting systems and world's literature classified myopia as a certain side effect. Conclusion Considering the current literature, it is not possible to define a clear correlation between the use of retinoids and the development or worsening of myopia. Some studies suggest that retinoids may cause a myopic shift and the pathophysiologyical mechanism is supported by some animal and in vitro studies, but there is a lack of large prospective and well-controlled studies. In case of ocular disturbances after retinoid use a prompt ophthalmological referral is advisable and in case of the detection of a myopic refractive error a relationship to retinoids should be ruled out, considering also other possible causes such as age and previous refractive status.

EDITORIAL article Front. Aging Neurosci., 16 May 2022Sec. Neurocognitive Aging and Behavior https://doi.org/10.3389/fnagi.2022.919775

Glaucoma is a multifactorial optic neuropathy characterized by the continuous loss of retinal ganglion cells, leading to progressive and irreversible visual impairment. In this minireview, we report the results of the most recent experimental studies concerning cells, molecular mechanisms, genes, and microbiome involved in neuroinflammation processes correlated to glaucoma neurodegeneration. The identification of cellular mechanisms and molecular pathways related to retinal ganglion cell death is the first step toward the discovery of new therapeutic strategies. Recent experimental studies identified the following possible targets: adenosine A 2A receptor, sterile alpha and TIR motif containing 1 (neurofilament light chain), toll-like receptors (TLRs) 2 and 4, phosphodiesterase type 4 (PDE4), and FasL-Fas signaling (in particular ONL1204, a small peptide antagonist of Fas receptors), and therapies directed against them. The continuous progress in knowledge provides interesting data, although the total lack of human studies remains an important limitation. Further research is required to better define the role of neuroinflammation in the neurodegeneration processes that occur in glaucomatous disease and to discover neuroprotective treatments amenable to clinical trials. The hereinafter reviewed studies are reported and evaluated according to their translational relevance.

BACKGROUND: The aim of the study is to evaluate the diagnostic ability of OCT parameters and retinal ganglion cells (RGCs) count in identify glaucomatous disease in myopic preperimetric eyes.METHODS: This was a cross-sectional observational study. The study group consisted of 154 eyes: 36 controls, 64 preperimetric (PPG), and 54 primary openangle glaucoma (POAG) eyes. Each group was divided into three subgroups based on axial length: emmetropic, myopic with axial length (AL) <25 mm, and myopic with AL>25 mm, to analyze the effect of myopia. The RGCs count was obtained using a model described later. As regard the influence of myopia on OCT parameters and RGC count, we performed Pearson’s correlation. The Area Under Receiver Operator Characteristics Curves (AUROC curves) evaluated which parameter had the best sensitivity and specificity in identifying glaucoma in myopic eyes.RESULTS: In Pearson’s test, all Ganglion Cell Complex (GCC) thicknesses showed the weakest and less significant correlation with AL in all groups. All the AUROCs were statistically significant, and above 0.5. Inferior GCC and Global Loss Volume (GLV) showed the highest AUCs in all myopic group and the best diagnostic ability in distinguishing control from glaucomatous eyes. RGCcount showed good AUROC in all groups, with sensitivities of about 83% in myopic eyes, and specificity over 91% in all groups. CONCLUSIONS: GCC is the parameter less influenced by the AL, and the inferior GCC and the GLV have the best diagnostic performance. The RGCcount has good sensitivity and specificity, so it can be used as a complementary test in the diagnosis of glaucoma in myopic preperimetric eyes.

Background. Glaucoma is a multifactorial optic neuropathy, which causes a continuous loss of retinal ganglion cells. Given the neurodegenerative nature of glaucoma, the necessity for neuroprotective intervention still arises, to be added alongside hypotonic therapy. Objective. The objective of this study was to assess the effect of daily intake of a homotaurine, carnosine, forskolin, vitamins B1, B2, and B6, folic acid, and magnesium based supplement (GANGLIOLIFE®) on the progression rates of the visual field in patients with progressive POAG despite good tonometric compensation and to assess the most suitable dosage. Methods. This is a monocentric nonrandomized experimental clinical study. Patients with mean deviation (MD) ranging from −2 dB to −15 dB with MD progression ≥1 dB in the previous year and IOP values of ≤18 mm Hg were included. All the patients underwent supplement therapy for a period of 6 months. For the first 2 months, they took 2 tablets a day, and for the following 4 months, 1 tablet a day. The patients were assessed before the start of treatment, time 0 (T0), after 2 months (T1), and after 6 months (T2) of therapy. At each check-up, patients were given a full eye test including perimetry, RNFL, and GCC using FD-OCT, PERG, contrast sensitivity, and QoL evaluation using the Glaucoma Symptom Scale questionnaire and National Eye Institute Visual Function Questionnaire 25. Results. 31 patients with a mean age of 70.80 ± 8.77 were included. At T1 and T2, the mean values of MD were lessened (MD = −5.37 ± −2.91, P<0.01, and MD = −5.48 ± 3.15, P<0.05, respectively) compared to T0 (MD = -5.98 ± 2.83). Patients also demonstrated a significant reduction in IOP (P<0.01), improved light sensitivity (P<0.01) and contrast sensitivity (P<0.05), and a better quality of life (P<0.05). Conclusions. Treatment with a supplement which includes homotaurine, carnosine, forskolin, vitamins B1, B2, and B6, folic acid, and magnesium has been shown to be able to slow down the rate of progression of functional damage and improve visual function after 2 and 6 months of daily intake. Quality of life showed significant improvement.

BACKGROUND: The aim of the study is to evaluate the diagnostic ability of OCT parameters and retinal ganglion cells (RGCs) count in identify glaucomatous disease in myopic preperimetric eyes.METHODS: This was a cross-sectional observational study. The study group consisted of 154 eyes: 36 healthy, 64 preperimetric (PPG), and 54 primary openangle glaucoma (POAG) eyes. Each group was divided into three subgroups based on axial length: emmetropic, myopic with axial length (AL) <25 mm, and myopic with AL>25 mm, to analyze the effect of myopia. The RGCs count was obtained using a model described later. As regard the influence of myopia on OCT parameters and RGC count, we performed Pearson’s correlation. The Area Under Receiver Operator Characteristics Curves (AUROC curves) evaluated which parameter had the best sensitivity and specificity in identifying glaucoma in myopic eyes.RESULTS: In Pearson’s test, all Ganglion Cell Complex (GCC) thicknesses showed the weakest and less significant correlation with AL in all groups. All the AUROCs were statistically significant, and above 0.5. Inferior GCC and Global Loss Volume (GLV) showed the highest AUCs in all myopic group and the best diagnostic ability in distinguishing healthy from glaucomatous eyes. RGCcount showed good AUROC in all groups, with sensitivities of about 83% in myopic eyes, and specificity over 91% in all groups.CONCLUSIONS: GCC is the parameter less influenced by the AL, and the inferior GCC and the GLV have the best diagnostic performance. The RGCcount has good sensitivity and specificity, so it can be used as a complementary test in the diagnosis of glaucoma in myopic preperimetric eyes.

PURPOSE:To evaluate papillary, peripapillary, and macular vasculature with optical coherence tomography angiography in preperimetric (PPG), primary open-angle glaucoma (POAG), and normal eyes, and to assess diagnostic ability and associations among the vasculature and structural damage.METHODS:This was an observational, cross-sectional study. Retinal nerve fiber layer (RNFL), ganglion cell complex thickness, whole-image (wiVD), inside disc (idVD), peripapillary (ppVD), and macular vessel densities were obtained. Analysis of variance, post hoc test, and Pearson coefficient were used. The areas under the receiver operating characteristic curve (AUC) and cut-offs were calculated.RESULTS:Thirteen healthy, 39 PPG, and 19 POAG eyes were included. Papillary and peripapillary VD were lower in POAG eyes in all parameters analyzed. wiVD in PPG eyes (52.37 ± 5.04%) was significantly decreased compared to healthy eyes (58.02 ± 2.02%, p < 0.05). AUC ranged from 0.62 to 0.90; the established cut-off values were 56% for wiVD, 55% for idVD, and 62% for ppVD. Pearson's correlation coefficient showed a direct correlation between the papillary or peripapillary VD and RNFL thickness.CONCLUSIONS:Vessel densities in POAG eyes are significantly lower than in healthy eyes, and they show good discriminatory abilities. A diminished microvascular network is associated with RNFL thinning more strongly in POAG than in PPG eyes.

SIGNIFICANCE:This study determined the impact of visual disabilities caused by glaucoma on the patient's everyday life and emphasized the importance of developing strategies to improve reading ability in primary open-angle glaucoma (POAG) patients.PURPOSE:The purposes of this study were to investigate the reading performances of patients affected by POAG using the Italian version of the Radner Reading Charts and to test the presence of correlation between visual field (VF) damage and reading parameters.METHODS:In this cross-sectional observational study, all patients underwent a complete ophthalmic evaluation including VF testing and evaluation of reading performance using the Radner Reading Charts. The parameters for testing reading performance were reading acuity in logRAD, reading speed in words per minute, maximum reading speed, critical print size, and reading mistakes. Primary open-angle glaucoma and healthy groups were compared using the Mann-Whitney U test. The correlation between VF and reading parameters in glaucomatous eyes was assessed using Spearman correlation analysis. Based on VF mean deviation, each POAG patient had differences in reading performance between his/her best and worst eyes when compared using the paired Wilcoxon test. Statistical significance was set at P ≤ .05.RESULTS:Eighty POAG patients and 60 healthy controls were enrolled. Glaucomatous subjects read slowly (166.63 ± 29.40 vs. 193.84 ± 26.20 words per minute, P < .0001) and made more mistakes than did healthy subjects. The critical print size for POAG patients was larger than the one for controls (0.52 ± 0.18 vs. 0.62 ± 0.16, P < .0001). Reading parameters showed a moderate correlation with VF mean deviation. The reading parameters were significantly impaired in the worst eye, and this result confirms the impact of VF loss on reading ability.CONCLUSIONS:This study demonstrated that glaucomatous patients read slowly and with more errors. Reading performances showed a good correlation with VF defect.

Background: Glaucoma is a leading cause of irreversible blindness worldwide. The increasing interest in the involvement of the cortical visual pathway in glaucomatous patients is due to the implications in recent therapies, such as neuroprotection and neuroregeneration. Objective: In this review, we outline the current understanding of brain structural, functional, and metabolic changes detected with the modern techniques of neuroimaging in glaucomatous subjects. Methods: We screened MEDLINE, EMBASE, CINAHL, CENTRAL, LILACS, Trip Database, and NICE for original contributions published until 31 October 2017. Studies with at least six patients affected by any type of glaucoma were considered. We included studies using the following neuroimaging techniques: functional Magnetic Resonance Imaging (fMRI), resting-state fMRI (rs-fMRI), magnetic resonance spectroscopy (MRS), voxel- based Morphometry (VBM), surface-based Morphometry (SBM), diffusion tensor MRI (DTI). Results: Over a total of 1,901 studies, 56 case series with a total of 2,381 patients were included. Evidence of neurodegenerative process in glaucomatous patients was found both within and beyond the visual system. Structural alterations in visual cortex (mainly reduced cortex thickness and volume) have been demonstrated with SBM and VBM; these changes were not limited to primary visual cortex but also involved association visual areas. Other brain regions, associated with visual function, demonstrated a certain grade of increased or decreased gray matter volume. Functional and metabolic abnormalities resulted within primary visual cortex in all studies with fMRI and MRS. Studies with rs-fMRI found disrupted connectivity between the primary and higher visual cortex and between visual cortex and associative visual areas in the task-free state of glaucomatous patients. Conclusions: This review contributes to the better understanding of brain abnormalities in glaucoma. It may stimulate further speculation about brain plasticity at a later age and therapeutic strategies, such as the prevention of cortical degeneration in patients with glaucoma. Structural, functional, and metabolic neuroimaging methods provided evidence of changes throughout the visual pathway in glaucomatous patients. Other brain areas, not directly involved in the processing of visual information, also showed alterations.

Chiea Chuen Khor, Tin Aung, Francesca Pasutto, Janey Wiggs and colleagues report a global genome-wide association study of exfoliation syndrome and a fine-mapping analysis of a previously identified disease-associated locus, LOXL1. They identify a rare protective variant in LOXL1 exclusive to the Japanese population and five new common variant susceptibility loci. Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 × 10−14) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10−8). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

Background: The effects of preservatives of antiglaucoma medications on corneal surface and tear function have been widely shown in literature; it's not the same as regards the active compounds themselves. The purpose of our study was to compare Ocular Surface Disease (OSD) signs and symptoms of Tafluprost 0.0015% versus preservative free (PF) Timolol 0.1% eyedrops in ocular hypertensive (OH) and in primary open-angle glaucoma (POAG) patients.Methods: A cross-sectional study included patients in monotherapy for at least 36 months with Tafluprost 0.0015% (27) or PF Timolol 0.1% (24) and 20 healthy age and sex-matched volunteers. All subjects underwent clinical tests (Schirmer I and break-up time), in vivo confocal microscopy (IVCM) and were surveyed using Ocular Surface Disease Index (OSDI) and Glaucoma Symptoms Scale (GSS) questionnaires. The groups were compared with ANOVA, Kruskal-Wallis test, t-test, Mann-Whitney test and Bonferroni's adjustment of p-values.Results: No significant differences were found in questionnaires scores, clinical tests, IVCM variables between therapy groups. Tafluprost 0.0015% group showed significantly higher OSDI score, basal epithelial cells density, stromal reflectivity, sub-basal nerves tortuosity (p = 0.0000, 0.037, 0.006, 0.0000) and less GSS score, number of sub-basal nerves (p = 0.0000, 0.037) than controls but similar clinical tests results (p > 0.05). PF Timolol group had significantly higher OSDI score, basal epithelial cells density, stromal reflectivity and sub-basal nerve tortuosity (p = 0. 000, 0.014, 0.008, 0.002), less GSS score, BUT and number of sub-basal nerves (p = 0.0000, 0.026, 0.003) than controls.Conclusions: Compared to PF Timolol 0.1%, Tafluprost 0.0015% showed similar safety with regards to tear function and corneal status and a similar tolerability profile. Both therapy groups show some alterations in corneal microstructure but no side effects on tear function except for an increased tear instability in PF Timolol 0.1% group. Ophtalmologists should be aware that even PF formulations may lead to a mild ocular surface impairment.

There is a lack of information about long‐term results of chronic angle closure glaucoma following an acute primary angle closure attack in Caucasian patients.

Objective To evaluate the efficacy and safety of the Xen Gel Stent and provide a macro- and microscopic analyses of bleb morphology. Methods A prospective 12-month study on patients with primary open-angle glaucoma. Patients underwent implantation of the XEN Gel Stent (Allergan INC, Dublin, Ireland) either alone or combined with a cataract surgery. Biomicroscopy, in vivo confocal microscopy (IVCM), and anterior segment-optical coherence tomography (AS-OCT) were used to assess bleb morphology. Safety parameters were adverse events, best corrected visual acuity, visual field, and corneal endothelial cell loss. A postoperative IOP ≤ 18 mmHg without or on medications was respectively defined as complete and qualified success while an IOP ≥ 18 mmHg was defined as failure. Results Twelve eyes of 11 patients were evaluated. At one year, 5 out of 10 patients available achieved a complete success while five were qualified success. AS-OCT showed that bleb wall reflectivity was significantly higher in the failure group; IVCM revealed that stromal density was significantly lower in the success group. No safety issues were recorded. Conclusion Implantation of the XEN Gel Stent appears to be a safe and effective procedure. AS-OCT and IVCM may be helpful in bleb assessment.