Paolo Frezzotti

<h3>Purpose</h3> To evaluate the long-term effects of preservative-free and preservative-containing antiglaucoma eye drops on the tear secretion and ocular surface. <h3>Design</h3> Comparative retrospective study. <h3>Methods</h3> A total of 84 patients with bilateral primary open-angle glaucoma or ocular hypertension divided into 5 groups according to type of topical hypotensive therapy and 20 healthy age-matched volunteers were studied. Clinical tests (corneal sensitivity, Schirmer I test, and lachrymal film break-up time), and in vivo confocal microscopy were performed in all patients. <h3>Results</h3> A significant reduction of the scores was found between groups on topical hypotensive therapy and the control group in all clinical parameters studied (<i>P</i> < .05). In particular, the clinical scores were significantly lower in the preservative medication groups than in the preservative-free group (<i>P</i> < .05). The density of superficial epithelial cells was reduced in all glaucomatous patients, except for the preservative-free group (<i>P</i> > .05), with respect to control subjects (<i>P</i> < .001). On the contrary, the density of basal epithelial cells of glaucomatous preservative therapy groups was higher than control and preservative-free groups (<i>P</i> < .05). Stromal keratocyte activation and the number of beads were higher in all glaucoma preservative groups (<i>P</i> < .05). The number of sub-basal nerves was lower in all glaucoma groups than in the control group (<i>P</i> < .05) and tortuosity was significantly higher in glaucoma than control groups (<i>P</i> < .05). Reflectivity of fibers did not show any significant difference between the 6 groups (<i>P</i> < .05). <h3>Conclusions</h3> Glaucomatous patients with chronic treatment show ocular surface alterations. The development of nontoxic antiglaucoma treatment may reduce damage to the ocular surface and improve the compliance and the adherence in the medical therapy.

To examine the circadian intraocular pressure (IOP) patterns in healthy subjects, in primary open angle and normal tension glaucoma (POAG; NTG) using a contact lens sensor (CLS; Sensimed Triggerfish, Lausanne, Switzerland).This was an observational, nonrandomized study. Ten healthy subjects (Group 1, 10 eyes) and 20 glaucomatous patients [20 eyes, 10 with POAG (Group 2) and 10 with NTG (Group 3)] were enrolled. All patients were controlled with prostaglandin analogues. The 24-hr IOP pattern was the main outcome. The morning (6AM-11AM), afternoon/evening (noon-11PM) and night (midnight-5AM) subperiod patterns, peaks and prolonged peaks (>1 hr) were secondary outcomes.Mean 24-hr IOP pattern showed a nocturnal acrophase in all groups. Patterns were significantly different among groups (p = 0.02), with highest nocturnal IOP values in POAG. Prolonged peaks were more common in patients with glaucoma (70%) than in healthy subjects (33.3%) (p < 0.001). Significant differences were found for Groups 2 and 3 in the morning versus afternoon/evening (p = 0.019 and p = 0.035, Bonferroni correction), morning versus night (p = 0.005 and p < 0.0001) and afternoon/evening versus night periods comparisons (p < 0.0001 for both groups). In Group 1, patterns significantly differed in the morning versus night and afternoon/evening versus night period comparisons (p < 0.0001).Continuous 24-hr IOP monitoring with the CLS revealed a nocturnal acrophase in healthy subjects and, more markedly, in glaucoma. Because the diurnal IOP profile seems not to predict the nocturnal rhythm, the circadian IOP pattern should be evaluated in clinical practice. These findings may be worthwhile for the management of glaucoma.

In order to test the hypothesis that in primary open angle glaucoma (POAG), an important cause of irreversible blindness, a spreading of neurodegeneration occurs through the brain, we performed multimodal MRI and subsequent whole-brain explorative voxelwise analyses in 13 advanced POAG patients and 12 age-matched normal controls (NC). Altered integrity (decreased fractional anisotropy or increased diffusivities) of white matter (WM) tracts was found not only along the visual pathway of POAG but also in nonvisual WM tracts (superior longitudinal fascicle, anterior thalamic radiation, corticospinal tract, middle cerebellar peduncle). POAG patients also showed brain atrophy in both visual cortex and other distant grey matter (GM) regions (frontoparietal cortex, hippocampi and cerebellar cortex), decreased functional connectivity (FC) in visual, working memory and dorsal attention networks and increased FC in visual and executive networks. In POAG, abnormalities in structure and FC within and outside visual system correlated with visual field parameters in the poorer performing eyes, thus emphasizing their clinical relevance. Altogether, this represents evidence that a vision disorder such as POAG can be considered a widespread neurodegenerative condition.

Abstract Our aim was to assess in primary open angle glaucoma (POAG), a major cause of irreversible blindness worldwide, whether diffuse brain changes recently shown in advanced stage can be detected since the early stage. We used multimodal magnetic resonance imaging (MRI) in 57 patients with the three POAG stages and in 29 age‐matched normal controls (NC). Voxelwise statistics was performed with nonparametric permutation testing. Compared with NC, disrupted anatomical connectivity (AC) was found in the whole POAG group along the visual pathway and in nonvisual white matter tracts ( P &lt; 0.001). Moreover, POAG patients showed decreased functional connectivity (FC) in the visual ( P = 0.004) and working memory ( P &lt; 0.001) networks whereas an increase occurred in the default mode ( P = 0.002) and subcortical ( P &lt; 0.001) networks. Altered AC and FC were already present in early POAG ( n = 14) in both visual and nonvisual systems ( P ≤ 0.01). Only severe POAG ( n = 30) showed gray matter atrophy and this mapped on visual cortex ( P &lt; 0.001) and hippocampus ( P &lt; 0.001). Increasing POAG stage was associated with worsening AC in both visual and nonvisual pathway ( P &lt; 0.001), progressive atrophy in the hippocampus and frontal cortex ( P &lt; 0.003). Most of the structural and functional alterations within and outside the visual system showed correlation ( P &lt; 0.001 to 0.02) with computerized visual field and retinal nerve fiber layer thickness. In conclusion, the complex pathogenesis of POAG includes widespread damage of AC and altered FC within and beyond the visual system since the early disease stage. The association of brain MRI changes with measures of visual severity emphasizes the clinical relevance of our findings. Hum Brain Mapp 37:4581–4596, 2016 . © 2016 Wiley Periodicals, Inc.

To compare the reduction of intraocular pressure (IOP) and glaucoma medications following selective laser trabeculoplasty (SLT) versus stand-alone placement of the Hydrus microstent, a microinvasive glaucoma surgery device.Prospective interventional case-series. University practice.Fifty six eyes (56 patients) with uncontrolled primary open-angle glaucoma.Patients received either SLT (n = 25) or Hydrus implantation (n = 31) in two centres. Patients were evaluated at baseline and 1, 7 days, 1, 3, 6 and 12 months after surgery.Intraocular pressure and number of glaucoma medications variations inter-groups and intra-groups.There were no significant differences at baseline between groups, but the mean deviation was worse in the Hydrus group (-8.43 ± 6.84 dB, confidence limits (CL)-2.8/-3.3 vs.-3.04 ± 0.65 dB, CL-6/-10.8; P < 0.001). After 12 months, there was a significant decrease in IOP and medications in the Hydrus group compared with baseline values. In the SLT group, only the decrease in IOP was significant. There was 3-fold greater reduction in medication use in the Hydrus group compared with SLT (-1.4 ± 0.97 vs.-0.5 ± 1.05, P = 0.001). 47% of patients were medication free at 12 months in the Hydrus group (4% in the SLT group). No complications were recorded in the SLT group. In the Hydrus group, three patients experienced a temporary reduction of visual acuity post-operatively, and two patients had post-operative IOP spikes that resolved within one week.Both SLT and Hydrus implantation reduced IOP without serious adverse events. Hydrus implantation led to a significant and further reduction in medication dependence at 12 months.

The molecular events responsible for obstruction of aqueous humor outflow and the loss of retinal ganglion cells in glaucoma, one of the main causes of blindness worldwide, remain poorly understood. We identified a synonymous variant, c.765C>T (Thr255Thr), in ankyrin repeats and suppressor of cytokine signaling box-containing protein 10 (ASB10) in a large family with primary open angle glaucoma (POAG) mapping to the GLC1F locus. This variant affects an exon splice enhancer site and alters mRNA splicing in lymphoblasts of affected family members. Systematic sequence analysis in two POAG patient groups (195 US and 977 German) and their respective controls (85 and 376) lead to the identification of 26 amino acid changes in 70 patients (70 of 1172; 6.0%) compared with 9 in 13 controls (13 of 461; 2.8%; P = 0.008). Molecular modeling suggests that these missense variants change ASB10 net charge or destabilize ankyrin repeats. ASB10 mRNA and protein were found to be strongly expressed in trabecular meshwork, retinal ganglion cells and ciliary body. Silencing of ASB10 transcripts in perfused anterior segment organ culture reduced outflow facility by ∼50% compared with control-infected anterior segments (P = 0.02). In conclusion, genetic and molecular analyses provide evidence for ASB10 as a glaucoma-causing gene.

Abstract Brain changes within and beyond the visual system have been demonstrated in primary open angle glaucoma (POAG), the most common type of glaucoma. These changes have been often interpreted as a neurodegenerative process due, at least partially, to the raised intraocular pressure (IOP). In this context, normal tension glaucoma (NTG), a form of POAG with IOP &lt;21 mm Hg despite the typical glaucomatous findings, represents the most suitable model of glaucoma to test the validity of this hypothesis. We acquired multimodal brain MRI in NTG patients ( n = 17) and compared them with demographically matched groups of POAG patients with raised IOP ( n = 17) and normal controls (NC, n = 29). Voxelwise statistics was performed with nonparametric permutation testing. Both NTG and POAG patients showed, compared to NC, significantly more gray matter atrophy in both the visual system and in nonvisual brain regions and altered diffusion tensor imaging‐derived anatomical connectivity (AC; lower fractional anisotropy and/or higher diffusivities). Compared with NTG, POAG had both more atrophic visual cortex and higher axial diffusivity in nonvisual regions. Functional connectivity (FC) with respect to NC was altered in NTG at short‐range level [visual network (VN), ventral attention network] and in POAG at long‐range level (between secondary VN and limbic network). FC of POAG was higher than NTG in both VN and executive network. This study provides further evidence that diffuse structural and functional abnormalities across glaucoma brain may be, at least partially, independent of raised IOP and the consequent retinal degeneration. This further defines glaucoma as a condition with neurodegeneration spreading. Hum Brain Mapp 39:532–541, 2018 . © 2017 Wiley Periodicals, Inc.

To evaluate frequency, conversion rate, and risk factors for blindness in glaucoma patients treated in European Universities.This multicenter retrospective study included 2402 consecutive patients with glaucoma in at least one eye. Medical charts were inspected and patients were divided into those blind and the remainder ('controls'). Blindness was defined as visual acuity≤0.05 and/or visual field loss to less than 10°.Unilateral and bilateral blindness were respectively 11.0% and 1.6% at the beginning, and 15.5% and 3.6% at the end of the observation period (7.5±5.5 years, range:1-25 years); conversion to blindness (at least unilateral) was 1.1%/year. 134 eyes (97 patients) developed blindness by POAG during the study. At the first access to study centre, they had mean deviation (MD) of -17.1±8.3 dB and treated intraocular pressure (IOP) of 17.1±6.6 mmHg. During follow-up the IOP decreased by 14% in these eyes but MD deteriorated by 1.1±3.5 dB/year, which was 5-fold higher than controls (0.2±1.6 dB/year). In a multivariate model, the best predictors for blindness by glaucoma were initial MD (p<0.001), initial IOP (p<0.001), older age at the beginning of follow-up (p<0.001), whereas final IOP was found to be protective (p<0.05).In this series of patients, blindness occurred in about 20%. Blindness by glaucoma had 2 characteristics: late diagnosis and/or late referral, and progression of the disease despite in most cases IOP was within the range of normality and target IOP was achieved; it could be predicted by high initial MD, high initial IOP, and old age.

Although lysyl oxidase-like 1 (LOXL1) is known as the principal genetic risk factor for pseudoexfoliation (PEX) syndrome, a major cause of glaucoma and cardiovascular complications, no functional variants have been identified to date. Here, we conduct a genome-wide association scan on 771 German PEX patients and 1,350 controls, followed by independent testing of associated variants in Italian and Japanese data sets. We focus on a 3.5-kb four-component polymorphic locus positioned spanning introns 1 and 2 of LOXL1 with enhancer-like chromatin features. We find that the rs11638944:C>G transversion exerts a cis-acting effect on the expression levels of LOXL1, mediated by differential binding of the transcription factor RXRα (retinoid X receptor alpha) and by modulating alternative splicing of LOXL1, eventually leading to reduced levels of LOXL1 mRNA in cells and tissues of risk allele carriers. These findings uncover a functional mechanism by which common noncoding variants influence LOXL1 expression.

This prospective study was conducted to evaluate the efficacy and safety of transscleral diode laser cyclophotocoagulation (TDLCP) in advanced refractory glaucoma.A total of 124 eyes in 121 patients with advanced glaucoma refractory to medical treatment were treated consecutively with TDLCP. Success was defined as final intraocular pressure (IOP) of 5-21 mmHg in eyes with visual acuity (VA) of more than hand movements (HM) and relief of pain in eyes with VA of HM or less, including blind eyes.Mean patient age was 65.6 +/- 17.1 years (range 14-91 years). Mean follow-up was 17 +/- 14.6 months (range 3-42 months). Mean pretreatment IOP was 29.9 +/- 8.4 mmHg (range 17-58 mmHg) and IOP at last follow-up was 20.8 +/- 8 mmHg (range 6-45 mmHg) (p < 0.001). The number of laser applications (mean 9.2 +/- 2.8, range 4-15) and maximal laser power (mean 2.01 +/- 0.22 mW, range 1.3-3.0 mW) were not associated with lower postoperative IOP. Intraocular pressure of < or = 21 mmHg was recorded in 63.0% of eyes at the last follow-up visit. Overall, 28 (21.7%) eyes required at least one retreatment. No phthisis bulbi or persistent hypotonia developed.TDLCP is an effective and safe method for the treatment of advanced refractory glaucoma, although repeated treatments are often necessary.

<h3>Aim</h3> To investigate, using laser scanning confocal microscopy (LSCM), the morphological changes of meibomian glands (MGs) in patients with glaucoma. <h3>Methods</h3> A total of 80 patients who were glaucomatous were enrolled, and 20 healthy subjects were used as controls. After completing an Ocular Surface Disease Index (OSDI) questionnaire, all subjects underwent tear film break-up time (BUT), fluorescein staining, Schirmer test I (STI) and LSCM examination of the MGs. The main outcome measures were: eyelid margin epithelial cell density, mean acinar density (MAD) and area (MAA), glandular orifice area, secretion reflectivity and inhomogeneous appearance of interstice and acinar wall. <h3>Results</h3> According to the number of anti-glaucoma medications they were taking, patients were divided into three groups: group 1 (30 eyes), one drug; group 2 (23 eyes), two drugs; group 3 (27 eyes), three or more drugs. LSCM showed lower MAD and MAA, greater secretion reflectivity and glandular orifice area in groups 2 and 3 than in controls (p&lt;0.05). The inhomogeneity of the interstice and acinar wall was significantly greater in all groups compared to controls (p&lt;0.05). Preserved prostaglandin analogues (PGAs) induced more pronounced modifications of all parameters than preservative free (PF)-PGAs (p&lt;0.05). No significant differences were found between preserved and PF-β-blockers. Significant relations were found among MAD, MAA, secretion reflectivity and OSDI score, BUT and ST (p&lt;0.05) and between secretion reflectivity and orifice area (p&lt;0.001). <h3>Conclusions</h3> In vivo LSCM is an effective tool in revealing morphological changes of MGs induced by anti-glaucoma medications. Given the key role in the ocular surface health, the evaluation of MG status in patients who are glaucomatous is worthwhile.

Intraocular pressure (IOP) results from a dynamic balance between aqueous humor formation and outflow. The simplest technique to measure IOP is indentation tonometry. Another technique is applanation. These methods are related to the elasticity of the eye, which mainly depends on its thickness and hysteresis. For several decades, Goldmann applanation tonometry has been the most accepted method of measuring IOP; the Goldmann tonometer is still used in all important trials. The relationship between IOP values and central corneal thickness (CCT) is well known; Goldmann stated that this relationship only holds for an average corneal thickness of 520 microm measured by optical pachymetry. The Ocular Hypertension Treatment Study (OHTS) showed that CCT is an important risk factor for a change from ocular hypertension to primary open-angle glaucoma. In a multivariate model that included IOP, CCT was the most powerful component of the predictive model. In the Early Manifest Glaucoma Trial (EMGT) with an 11-year follow-up, CCT was a significant predictive factor for glaucoma progression in patients with higher baseline IOP but not in those with lower baseline IOP. Clinical trials such as the OHTS and EMGT cannot prove that CCT is linked to a risk for glaucoma on a biological level. Thus, in eyes with glaucoma, IOP must be treated because it has a significant influence on progression of glaucoma, regardless of the baseline IOP and CCT.

Purpose: To determine whether there were ocular surface changes in glaucomatous patients treated with preservatives beta-blockers who switched to preservative-free beta-blockers. Methods: This was a prospective, longitudinal, open-labeled study. One hundred thirty-two patients with primary open angle glaucoma treated with a preserved beta-blocker were enrolled. All the patients underwent perimetric and gonioscopic examination, complete ophthalmologic examination, intraocular pressure (IOP) measurements, evaluation of ocular surface, Schirmer's test, blood pressure and heart rate at baseline and 1–3 months after changing the medical treatment to a preservative-free timolol 0.1% (Timogel 0.1; Thea). At baseline, after 1 month and at the end of the study (3 months), all patients underwent a questionnaire on the visual quality and symptoms and on the quality of life (QoL). Data were analyzed by t-test when the distribution of the data was normal, by Mann–Whitney when the distribution was not normal. Results: No significant difference was found for IOP before switching from preserved beta-blockers to preservative-free ones. No significant difference was found in blood pressure and heart rate. However, a statistically significant difference was found for abnormal fluorescein staining of the cornea and conjunctiva, eyelid erythema, conjunctival hyperemia, and follicular hyperplasia. A significant difference was found for break-up time (from 9.38±4.7 s at baseline to 10.64±4.7 s after 3 months) and Schirmer's test (from 12.9±5.96 mm at baseline to 14.2±5.87 mm after 3 months). The questionnaire showed that the patient improved the dryness and foreign body sensation. Conclusion: In glaucomatous patients, preservative-free 0.1 timolol treatment improved their QoL. Similar dry eye signs or symptoms improved after 3 months of treatment reducing dryness, hyperemia, follicular hyperplasia, and foreign body sensation.

To evaluate the effects at 1 year of preservative-free timolol gel and preserved timolol eye drops on conjunctiva and tear parameters.Forty patients with primary open-angle glaucoma or ocular hypertension were randomized to the two treatment groups and compared with 20 healthy age-matched controls. Clinical tests (IOP, Schirmer I test, and lacrimal film break-up time BUT) and in vivo conjunctival confocal microscopy (IVCM) were performed in all patients at baseline and after 12 months. IVCM (HRT II Rostock Cornea Module; Heidelberg Engineering GmbH, Heidelberg, Germany) was performed after topical anaesthesia in the four cardinal locations and at the corresponding limbus to analyse conjunctiva cells. The main IVCM outcomes were goblet cell density and epithelial regularity.IVCM and clinical parameters were similar in the three groups at baseline. After 12 months, intra-epithelial goblet cell density was significantly lower in the preserved (48.25 ± 7.70) than in the preservative-free beta-blocker group (86.83 ± 22.17, p < 0.001) and controls (88.9 ± 18.33, p < 0.001). The epithelial layer was significantly more regular in the preserved beta-blocker medication group than in the preservative-free beta-blocker group (p < 0.001) and the control group (p < 0.001). A significant reduction in both Schirmer I and BUT was found in the group of preserved timolol (respectively, 11.3 ± 2.97 and 8.12 ± 0.99) compared with preservative-free timolol (16.8 ± 1.83 and 11.27 ± 1.27, p < 0.001) and controls (17.8 ± 1.87 and 12.10 ± 1.28, p < 0.001).Based on our IVCM data, preservative-free beta-blocker gel induces less changes at ocular surface than preserved beta-blockers, a fact that should be considered to obtain less adverse effects and maximal adherence to treatment in a chronic condition such as glaucoma.

As a progressive condition, glaucoma may impair health-related quality of life (HRQoL), due to vision loss and other factors. This study evaluated HRQoL in a cohort of patients treated for primary open-angle glaucoma (POAG) and assessed its association with clinical features.This was an Italian, multicentre, cross-sectional, observational study with the subgroup of newly diagnosed patients with POAG prospectively followed up for one year. Patients with previous or new diagnosis (or strong clinical suspicion) of POAG aged >18 years were considered eligible. Information was collected on demographic characteristics, medical history, clinical presentation and POAG treatments. HRQoL was measured using the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ-25) and Glaucoma Symptom Scale (GSS). Subscale and total scores were obtained and a Pearson correlation coefficient between instruments' scores calculated.A total of 3227 patients were enrolled from 2012 to 2013 and 3169 were analysed. Mean age was 66.9 years. A total of 93.8% had a previous diagnosis (median duration: 8.0 years). Median values for mean deviation and pattern standard deviation were 3.9 and 3.6 dB, respectively. Mean scores on most subscales of the NEI-VFQ-25 exceeded 75.0 and mean GSS subscale scores ranged between 70.8 and 79.7 (with a total mean score of 74.8). HRQoL scores on both scales were significantly inversely associated with POAG severity.In this large sample of Italians treated for POAG, disease severity was limited and HRQoL scores were high. QoL decreased with advancing disease severity. These findings confirm the role of vision loss in impairing QoL in POAG, underlying the importance of timely detection and appropriate treatment.

We analyzed the preoperative conjunctival goblet cell density (GCD), MUC5AC, and HLA-DR in glaucomatous patients undergoing trabeculectomy, using laser scanning confocal microscopy (LSCM) and impression cytology (IC).We enrolled 57 patients undergoing trabeculectomy. At baseline LSCM and IC were performed at the site planned for surgery; LSCM was repeated after 12 months at the bleb site. The main outcomes were: GCD, mean microcyst density (MMD) and area (MMA) at LSCM, MUC5AC, and HLA-DR positivity at IC, and IOP. The relationships between baseline GCD, and 12-month IOP, MMD, and MMA were analyzed.Trabeculectomy was successful in 39 patients (complete success in 27, Group 1; qualified in 12, Group 2), and unsuccessful in 18 (Group 3). At baseline IOP (mm Hg) was 27.2 ± 3.12, 27.5 ± 2.23, and 27.7 ± 1.90 in Groups 1 to 3, respectively; GCD and MUC5AC positivity were higher in Group 1 compared to Groups 2 and 3 (P < 0.05); HLA-DR, MMD, and MMA were not significantly different among the groups. At 12 months, IOP reduced by 45.3%, 35.4%, and 12.8% in Groups 1 to 3, respectively. Goblet cell density did not change in Group 1, whereas it was reduced in Groups 2 and 3 (P < 0.05), with values lower in Group 3. Mean microcyst density and MMA increased in Groups 1 and 2 (P < 0.05), with values higher in Group 1 (P < 0.05). Baseline GCD positively correlated with 12-month IOP reduction (P < 0.001, r = 0.641), MMD (P < 0.05, r = 0.454), and MMA (P < 0.001, r = 0.541).Goblet cells positively affect the filtration ability after trabeculectomy; therefore, preoperative GCD could be considered as a potential in vivo biomarker of surgical success.

Abstract LOXL1 (lysyl oxidase-like 1) has been identified as the major effect locus in pseudoexfoliation (PEX) syndrome, a fibrotic disorder of the extracellular matrix and frequent cause of chronic open-angle glaucoma. However, all known PEX-associated common variants show allele effect reversal in populations of different ancestry, casting doubt on their biological significance. Based on extensive LOXL1 deep sequencing, we report here the identification of a common non-coding sequence variant, rs7173049A&gt;G, located downstream of LOXL1, consistently associated with a decrease in PEX risk (odds ratio, OR = 0.63; P = 6.33 × 10−31) in nine different ethnic populations. We provide experimental evidence for a functional enhancer-like regulatory activity of the genomic region surrounding rs7173049 influencing expression levels of ISLR2 (immunoglobulin superfamily containing leucine-rich repeat protein 2) and STRA6 [stimulated by retinoic acid (RA) receptor 6], apparently mediated by allele-specific binding of the transcription factor thyroid hormone receptor beta. We further show that the protective rs7173049-G allele correlates with increased tissue expression levels of ISLR2 and STRA6 and that both genes are significantly downregulated in tissues of PEX patients together with other key components of the STRA6 receptor-driven RA signaling pathway. siRNA-mediated downregulation of RA signaling induces upregulation of LOXL1 and PEX-associated matrix genes in PEX-relevant cell types. These data indicate that dysregulation of STRA6 and impaired retinoid metabolism are involved in the pathophysiology of PEX syndrome and that the variant rs7173049-G, which represents the first common variant at the broad LOXL1 locus without allele effect reversal, mediates a protective effect through upregulation of STRA6 in ocular tissues.

To evaluate the long-term perimetric fluctuation (LF) in patients with different stages of glaucoma according to the Glaucoma Staging System 2 (GSS2).This multicentre retrospective study included 161 eyes of 161 stable glaucoma patients undergoing four visual-field tests (Humphrey SITA-Standard program over the central 24° or 30°) over a 2-year period. For each patient, the stage of the disease was classified according to GSS2. LF was then calculated as the mean of the standard deviations of point-to-point threshold sensitivities in the four repetitions. LF in GSS2 stages was compared using the t test. Results LF progressively increased from stage 0 to stage 4, and then decreased at stage 5. Stage 4 had a peak of 3.19 ± 0.94 dB, with statistically significant differences compared with all the other stages. The lowest LF (1.65 ± 0.60 dB) was found for normal subjects, whereas similar data were found for borderline patients and those at stages 1 and 5 (2.09 ± 0.58, 2.13 ± 0.57 and 2.22 ± 0.89 dB, respectively; p > 0.13). Visual fields with generalised defects had a lower LF (1.90 ± 0.81) than those with mixed (2.84 ± 0.87, p = 0.0003) and localised (2.63 ± 0.72, p = 0.004) defects. Conclusions In this study, the authors showed that the lower the visual-field defect, the lower was LF, except at stage 5 of GSS2. As test-retest changes exceeding LF could represent a sign of progression, the authors suggest that clinicians using this classification system calculate LF, in order to better differentiate true progression from variability.

To evaluate whether a difference in central corneal thickness (CCT) between the paired eyes could be associated to worse glaucoma in the thinner cornea eye.From 16 different glaucoma centres, at least 50 glaucomatous patients were saved on the Italian Glaucoma Register. Eight hundred and sixteen glaucomatous patients were found in the register. CCT, ophthalmoscopic cup/disc ratio, mean deviation (MD), pattern SD (PSD), and intraocular pressure (IOP). The difference (Δ) between the paired eyes was calculated for all the considered parameters and two subgroups were created on the basis of ΔCCT. Because the difference between the two eyes could be positive or negative, the absolute value of Δ was considered for all the measurements. Three different ΔCCT cutoffs were selected: 10, 15, and 20 μm. Student's t-test was used to compare the subgroups.When the entire group was divided in two subgroups using 20 μm as ΔCCT cutoff, no significant difference was found for ΔIOP (-0.38 ± 2.53 (mean ± SD) mm Hg and -0.07 ± 2.35 mm Hg, respectively) between the two subgroups. Significant (P<0.001) difference was found for ΔMD (6.58 ± 7.30 and 3.14 ± 4.22 dB, respectively), ΔPSD (3.92 ± 4.01 and 2.16 ± 2.57, respectively), and ΔC/D (0.11 ± 0.14 and 0.08 ± 0.11, respectively) between the two subgroups. No significant correlation was found between ΔCCT and the other parameters.The ΔCCT between the two eyes could be associated to a worse glaucoma in the thinner cornea eye.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is considered a genetic form of small-vessel disease causing subcortical dementia. A relevant role of axonal injury was recently proposed to explain disability and cognitive decline in this disease. The retinal nerve fiber layer (RNFL) is the only part of the brain where unmyelinated axons can be visualized and quantified in vivo. Their assessment may be an easily reproducible marker of neurodegenerative processes. The aim of this study was to investigate axonal degeneration in CADASIL by measuring RNFL thickness and correlating it with MRI measures of global and regional cerebral atrophy.RNFL thickness was measured using optical coherence tomography in 17 CADASIL patients. Average values per quadrant (temporal, superior, nasal, inferior) and overall values were compared with those of normal sex- and age-matched subjects. Data of 13 patients were analyzed for correlations with MRI-based global and regional brain volumes normalized for head size.RNFL thickness was significantly reduced in CADASIL patients with respect to controls (p < 0.05). No significant correlations were found between RNFL thinning and brain atrophy.RNFL thinning suggests that retinal axonal loss occurs in CADASIL, even in the absence of subjective visual deficit.

&lt;b&gt;&lt;i&gt;Purpose:&lt;/i&gt;&lt;/b&gt; To evaluate short-term intraocular pressure (IOP) changes after phacoemulsification in glaucoma and normal patients and the effect of oral acetazolamide (Diamox) to control IOP in these patients. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; 120 patients undergoing cataract surgery were included in this prospective multicenter study involving 6 University Eye Clinics: 60 patients with well-controlled primary open-angle glaucoma (POAG) and 60 controls. Half of the study participants received oral acetazolamide, 250 mg, 1 and 6 h after surgery. The treated and untreated groups were matched for age and density of cataract. All patients underwent a standard phacoemulsification procedure and were checked for IOP with Goldmann tonometry in the morning before surgery and then at 3, 6, 21 and 24 h postoperatively by a masked evaluator. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; The group with POAG showed a significant postsurgical increase in IOP (p &lt; 0.001) at all time points. Six of thirty (20%) untreated POAG patients showed at least 1 IOP reading above 30 mm Hg whereas acetazolamide significantly reduced postoperative IOP at all time points (p &lt; 0.01) and in no case was IOP &gt;30 mm Hg. The control group had high IOP during the first 6 h (p &lt; 0.01), but normal values thereafter. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; A significant short-term IOP increase may be found after phacoemulsification both in POAG and normal patients; this is not dangerous in normal subjects, but can be potentially dangerous in POAG patients. The use of systemic acetazolamide provided significant control of IOP and could be considered a ‘possible standard’ management of cataract surgery in POAG patients.

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.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%).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.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.

&lt;b&gt;&lt;i&gt;Aim:&lt;/i&gt;&lt;/b&gt; To investigate and compare the effects of topical benzalkonium chloride-preserved prostaglandins (PGAs) on the ocular surface in patients with primary open-angle glaucoma before and after 3 months of treatment with additional 0.5% preservative-free tamarind seed polysaccharide single-dose eyedrops (TSP®, Oftagen, Pisa, Italy). &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; This was a prospective, longitudinal, multicenter study. From 5 different Italian glaucoma centers, 10 glaucomatous patients were recruited in each center. All the patients were treated with a PGA with preservative for at least 1 year. Preservative-free artificial tears 3 times per day were prescribed. The participants were subjected to clinical and instrumental evaluation at baseline, after 1 month and after 3 months of treatment. All patients were examined with a digital corneal confocal laser scanning microscope (HRT II Rostock Cornea Module). &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; After 3 months of TSP 0.5% treatment, an improvement of some ocular signs and symptoms was found. The percentage of conjunctival hyperemia decreased from 67 to 13%. Schirmer's test and breakup time significantly changed from the baseline after 3 months. Confocal microscopy showed a significant increase in conjunctival goblet cells. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; Artificial substitutes, in particular TSP 0.5%, might protect the ocular surface hence giving higher compliance, adherence and quality of life to the patients.

PurposeTo evaluate and compare the diagnostic accuracy of the Humphrey Field Analyzer (HFA), Octopus perimetry, and Cirrus OCT for glaucomatous optic neuropathy.MethodsEighty-eight healthy individuals and 150 open-angle glaucoma patients were consecutive and prospectively selected. Eligibility criteria for the glaucoma group were intraocular pressure ≥21 mm Hg and glaucomatous optic nerve head morphology. All subjects underwent a reliable standard automated perimetry with the HFA and Octopus perimeter, and were imaged with the Cirrus OCT. Receiver-operating characteristic (ROC) curves were plotted for the threshold values and main indices of the HFA and Octopus, the peripapillary retinal nerve fiber layer thicknesses, and the optic nerve head parameters. Sensitivities at 85 and 95% fixed-specificities were also calculated. The best areas under the ROC curves (AUCs) were compared using the DeLong method.ResultsIn the glaucoma group, mean deviation (MD) was -5.42±4.6 dB for HFA and 3.90±3.6 dB for Octopus. The MD of the HFA (0.966; P<0.001), mean sensitivity of the Octopus (0.941; P<0.001), and average cup-to-disc (C/D) ratio measured by the Cirrus OCT (0.958; P<0.001) had the largest AUCs for each test studied. There were no significant differences among them. Sensitivities at 95% fixed-specificity were 82% for pattern standard deviation of the HFA, 81.3% for average C/D ratio of OCT, and 80% for the MD of the Octopus.ConclusionsHFA, Octopus, and Cirrus OCT demonstrated similar diagnostic accuracies for glaucomatous optic neuropathy. Visual field and OCT provide supplementary information and thus these tests are not interchangeable.

To assess the involvement of WDR36 sequence variance in primary open-angle glaucoma (POAG) in Italian patients.A cohort of 34 Italian families affected by POAG was analysed by denaturing high-performance liquid chromatography for mutation in the WDR36 gene. Among the 34 families enrolled, 25 were affected by high-tension glaucoma (HTG), four by juvenile open-angle glaucoma and one by normal tension glaucoma. In addition, four families presented both juvenile open-angle glaucoma and HTG-POAG patients within the same pedigree.Four previously identified intronic polymorphisms (IVS5+30C→T; IVS12+90 G→T; IVS13+89G→A; IVS16-30A→G) and a novel one (IVS21-75G→A) have been identified. In addition, one proband was found to carry the p.D658G mutation reported as the more recurrent disease-causing allele.The findings suggest that WDR36 sequence variance is only a rare cause of glaucoma in Italian families. Clearly, investigation of additional families with extensive studies is needed to clarify the role of WDR36 in the pathophysiology of glaucoma.

To examine the level of agreement among nine clinicians in assessing progressive deterioration in visual field (VF) overview using three different methods of analysis.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 patient's 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.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.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.

To assess repeatability (intra-observer variability) and reproducibility (inter-operator variability) of intraocular pressure (IOP) measurements with servo-controlled Bioresonator Applanation Resonance Tonometry (ART) and to evaluate possible influential factors. The study included 178 patients (115 glaucoma and 63 controls; one eye per subject). IOP was measured once with a Goldmann applanation tonometer (GAT) and twice by ART (ART1, ART2), in randomized sequence, by a single operator to assess intra-operator variability. Each ART measurement consisted on 3 readings. To assess inter-operator variability 2 evaluators performed 2 measurements each (in random order) on the same patient. Repeatability and reproducibility were assessed by the coefficient of variation (CoV) and intraclass correlation coefficient (ICC). In the entire cohort, ART1 was 0.4 ± 2.2 mmHg (−7.0 to 5.7 mmHg) higher than ART2 (p = 0.03) regardless of test order. Intra-operator CoV was 7.0% ± 6.3%, and ICC was 0.80-0.92. Inter-operator CoV ranged between 5.7% ± 6.1% and 8.2% ± 7.2%, and ICC between 0.86 and 0.97. ART1 and 2 were respectively 1.7 ± 3.1 and 1.3 ± 3.1 mmHg higher than GAT (p < 0.01). Test-retest difference with ART fell within ±1 mmHg in 41% of cases, within ±2 mmHg in 70%, within ±3 mmHg in 85%. 15% had a test-retest difference higher than ± 3 mmHg; Bland-Altman 95% intervals of confidence were −3.9 and +4.6 mmHg. Results were unaffected by age, diagnosis, central corneal thickness, keratometry, operator, randomization sequence. In most cases ART repeatability and reproducibility were high, with no differences due to patients' characteristics. ART measurements overestimated GAT by a mean of 1.3-1.7 mmHg.

Single nucleotide polymorphisms (SNPs) within the LOXL1 gene are associated with pseudoesfoliation syndrome and pseudoesfoliation glaucoma. The aim of our study is to investigate a potential involvement of LOXL1 gene in the pathogenesis of pigment dispersion syndrome (PDS) and pigmentary glaucoma (PG).A cohort of Caucasian origin of 84 unrelated and clinically well-characterised patients with PDS/PG and 200 control subjects were included in the study. Genomic DNA from whole blood was extracted and the coding and regulatory regions of LOXL1 gene were risequenced in both patients and controls to identify unknown sequence variations. Genotype and haplotype analysis were performed with UNPHASED software. The expression levels of LOXL1 were determined on c-DNA from peripheral blood lymphocytes by quantitative real-time RT-PCR.A significant allele association was detected for SNP rs2304722 within the fifth intron of LOXL1 (Odds ratio (OR = 2.43, p-value = 3,05e-2). Haplotype analysis revealed the existence of risk and protective haplotypes associated with PG-PDS (OR = 3.35; p-value = 1.00e-5 and OR = 3.35; p-value = 1.00e-4, respectively). Expression analysis suggests that associated haplotypes can regulate the expression level LOXL1.Haplotypes of LOXL1 are associated with PG-PDS independently from rs1048661, leading to a differential expression of the transcript.

It is generally accepted that dialysis may lower plasma osmolality at a faster rate than changes in ocular osmolality. This osmotic difference causes water to migrate from the plasma into the aqueous humor, increasing intraocular pressure. Certain authors have described IOP increase in patients with narrow angles. Here we report a neovascular glaucoma patient who experienced a substantial increase in IOP associated with severe eye pain and blurred vision during sessions of dialysis. The patient had been refractory to several antiglaucoma drugs and improved after intravenous administration of 20 % hyperosmotic glucose solution with dialysis and pan-retinal photocoagulation. It is the first report in which intravenous glucose administration and reduction of neovascularization by argon laser pan-retinal photocoagulation successfully managed IOP increase during dialysis in neovascular glaucoma. Further clinical studies are required to confirm our results.

We hypothesized that assessment of brain connectivity may shed light on the underpinnings of ocular hypertension (OHT), characterized by raised intraocular pressure (IOP) and no typical glaucomatous findings. OHT carries a risk for future glaucoma development, thus representing a model of presymptomatic condition. In previous studies on glaucoma, we showed altered brain connectivity since early stage and in case of normal IOP. In this pilot study, we used a multimodal MRI approach by modeling voxelwise measures of grey matter volume, anatomical connectivity along white matter tracts and large-scale functional connectivity in OHT subjects (n=18, age: 58.3±9.8 years) and demographically matched normal controls (n=29). While OHT brain had no structural alterations, nonetheless it showed significantly decreased functional connectivity in key cognitive networks (default mode network, frontoparietal working memory network, ventral attention network and salience network) and altered long-range functional connectivity, which was decreased between default mode and salience networks and increased between primary and secondary visual networks. Overall, such findings seem to delineate a complex neuroplasticity in the OHT brain, where decreased functional connectivity in nonvisual networks may reflect a type of temporarily downregulated functional reserve while increased functional connectivity between visual networks may be viewed as a very early attempt of adaptive functional reorganization of the visual system.

Objective . To compare the equivalent optic nerve head (OHN) parameters obtained with confocal scanning laser ophthalmoscopy (HRT3) and spectral-domain optical coherence tomography (OCT) in healthy and glaucoma patients. Methods . One hundred and eighty-two consecutive healthy subjects and 156 patients with open-angle glaucoma were divided into 2 groups according to intraocular pressure and visual field outcomes. All participants underwent imaging of the ONH with the HRT3 and the Cirrus OCT. The ONH parameters and the receiver operating characteristic (ROC) curves were compared between both groups. Results . Mean age did not differ between the normal and glaucoma groups (59.55 ± 9.7 years and 61.05 ± 9.4 years, resp.;<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"><mml:mi>P</mml:mi><mml:mo>=</mml:mo><mml:mn>0.15</mml:mn></mml:math>). Rim area, average cup-to-disc (C/D) ratio, vertical C/D ratio, and cup volume were different between both instruments (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M2"><mml:mi>P</mml:mi><mml:mo>&lt;</mml:mo><mml:mn>0.001</mml:mn></mml:math>). All equivalent ONH parameters, except disc area, were different between both groups (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M3"><mml:mi>P</mml:mi><mml:mo>&lt;</mml:mo><mml:mn>0.001</mml:mn></mml:math>). The best areas under the ROC curve were observed for vertical C/D ratio (0.980 for OCT and 0.942 for HRT3;<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M4"><mml:mi>P</mml:mi><mml:mo>=</mml:mo><mml:mn>0.11</mml:mn></mml:math>). Sensitivities at 95% fixed-specificities of OCT parameters were higher than those of HRT3. Conclusions . Equivalent ONH parameters of Cirrus OCT and HRT3 are different and cannot be used interchangeably. ONH parameters measured with OCT yielded a slightly better diagnostic performance.

Although cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is considered a cerebrovascular disorder with almost exclusively neurological symptoms, arteriopathy is generalized and also involves the choroid and retina.To study optic nerve head microvascular function in CADASIL by assessing blood flow, volume, and velocity with a retina flowmeter.Scanning laser Doppler flowmetry permits the noninvasive assessment of relative blood velocity, volume, and flow in a sample volume of either retina or anterior optic nerve head. Measurements were performed in a first group of 9 eyes of 5 patients with CADASIL and a second group of 8 eyes of 4 healthy subjects. Hemodynamic parameters were computed in 4 quadrants of the optic disc (superior nasal, superior temporal, inferior nasal, and inferior temporal). The Wilcoxon rank sum test was used to assess differences in relative flow, volume, and velocity in each quadrant and between the 2 groups and differences in overall optic nerve head blood flow, volume, and velocity.Patients with CADASIL had a significant decrease in overall blood flow and volume compared with healthy subjects (P<.05). The reduction in blood flow and volume was particularly significant in the superior and inferior temporal quadrants. No significant differences were found nasally between the patients and the control groups.Our results suggest that hemodynamic parameters are abnormal in the superficial nerve fiber layer of the optic nerve head of patients with CADASIL, especially in the temporal quadrants of the neuroretinal rim.

To report a case of isolated conjunctival Bowen disease treated with surgical resection and amniotic membrane transplantation.Interventional case report.A 70-year-old man was admitted to our clinic with a large conjunctival verrucous plaque well-demarcated in the correspondence of the bulbar conjunctiva in the superior quadrant of the left eye with involved limbal and corneal surface. Ophthalmologic examination on slit-lamp examination and color fundus photographs were carried out before surgery and the results were evaluated.Treatment options and treatment studies of Bowen disease are difficult because there are a variety of different protocols and the success of the management depends on several factors (body site, lesion size, number of lesions, and thickness). In the conjunctival localization of the lesion, amniotic membrane transplantation appears to be a useful therapeutic choice after surgical resection of the lesion used to reconstruct ocular and conjunctival surface.

Objective . To evaluate the relationship between spectral-domain optical coherence tomography (OCT) and standard automated perimetry (SAP) in healthy and glaucoma individuals. Methods . The sample comprised 338 individuals divided into 2 groups according to intraocular pressure and visual field outcomes. All participants underwent a reliable SAP and imaging of the optic nerve head with the Cirrus OCT. Pearson correlations were calculated between threshold sensitivity values of SAP (converted to linear scale) and OCT parameters. Results . Mean age did not differ between the control and glaucoma groups (59.55 ± 9.7 years and 61.05 ± 9.4 years, resp.;<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"><mml:mi>P</mml:mi><mml:mo>=</mml:mo><mml:mn>0.15</mml:mn></mml:math>). Significant differences were found for the threshold sensitivities at each of the 52 points evaluated with SAP (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M2"><mml:mi>P</mml:mi><mml:mo>&lt;</mml:mo><mml:mn>0.001</mml:mn></mml:math>) and the peripapillary retinal nerve fiber layer (RNFL) thicknesses, except at 3 and 9 clock-hour positions between both groups. Mild to moderate correlations (ranging between 0.286 and 0.593;<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M3"><mml:mi>P</mml:mi><mml:mo>&lt;</mml:mo><mml:mn>0.001</mml:mn></mml:math>) were observed between SAP and most OCT parameters in the glaucoma group. The strongest correlations were found between the inferior RNFL thickness and the superior hemifield points. The healthy group showed lower and weaker correlations than the glaucoma group. Conclusions . Peripapillary RNFL thickness measured with Cirrus OCT showed mild to moderate correlations with SAP in glaucoma patients.

Purpose To evaluate recent molecular genetic studies focused on localizing and identifying the genes involved in adult-onset primary glaucoma, characterizing the gene products, and investigating the molecular mechanisms implicated in the pathophysiology of the disease. METHODS Several studies have aimed at understanding gene expression and protein processing and attempting to correlate the mutations identified in the involved genes, particularly the TIGR/MYOC gene, with the overall spectrum of the disease, ranging from juvenile glaucoma to typical late-onset primary open-angle glaucoma. Genetic research lemains essential until highly specific and sensitive tests have been developed (plausible disease-causing sequence variations, polymorphisms). Results The most effective method for detecting glaucoma clinically is the study of optic nerve and visual field damage, as well as intraocular pressure. In subjects at high risk, in members of families with a strong history of inherited glaucoma, and in families with a MYOC-positive test, the result may represent a marker to assess presymptomatic diagnosis and may be useful as a prognostic marker. CONCLUSIONS OPTN seems to have a role confined to the pathogenesis of normotensive glaucoma with a few exceptions. Presently, the introduction of the expensive and time-consuming OPTN gene test in the current diagnosis of familial glaucoma is not justified.

The third author’s name is spelled incorrectly. The correct name should be: Giovanni Montesano. The correct citation should be: Rossetti L, Digiuni M, Montesano G, Centofanti M, Fea AM, Iester M, et al. (2015) Blindness and Glaucoma: A Multicenter Data Review from 7 Academic Eye Clinics. PLoS ONE 10(8): e0136632. doi:10.1371/journal.pone.0136632

Objective . To assess the intrasession repeatability and intersession reproducibility of peripapillary retinal nerve fiber layer (RNFL) thickness parameters measured by scanning laser polarimetry (SLP) with enhanced corneal compensation (ECC) in healthy and glaucomatous eyes. Methods . One randomly selected eye of 82 healthy individuals and 60 glaucoma subjects was evaluated. Three scans were acquired during the first visit to evaluate intravisit repeatability. A different operator obtained two additional scans within 2 months after the first session to determine intervisit reproducibility. The intraclass correlation coefficient (ICC), coefficient of variation (COV), and test-retest variability (TRT) were calculated for all SLP parameters in both groups. Results . ICCs ranged from 0.920 to 0.982 for intravisit measurements and from 0.910 to 0.978 for intervisit measurements. The temporal-superior-nasal-inferior-temporal (TSNIT) average was the highest (0.967 and 0.946) in normal eyes, while nerve fiber indicator (NFI; 0.982) and inferior average (0.978) yielded the best ICC in glaucomatous eyes for intravisit and intervisit measurements, respectively. All COVs were under 10% in both groups, except NFI. TSNIT average had the lowest COV (2.43%) in either type of measurement. Intervisit TRT ranged from 6.48 to 12.84. Conclusions . The reproducibility of peripapillary RNFL measurements obtained with SLP-ECC was excellent, indicating that SLP-ECC is sufficiently accurate for monitoring glaucoma progression.

Kearns-Sayre syndrome is characterized by chronic progressive external ophthalmoplegia, tapetoretinal degeneration and severe generalized myopathy.We report on a 82-year-old male patient with Kearns-Sayre syndrome with open angle glaucoma.Reports of primary open angle glaucoma with Kearns-Sayre syndrome are very rare, but it is difficult to believe that this association is merely coincidental.

The objective of this study was to assess preference for fixed-combination brinzolamide 1%/timolol 0.5% (BTFC) versus fixed-combination dorzolamide 2%/timolol 0.5% (DTFC) in patients with open-angle glaucoma or ocular hypertension.In this prospective, single-masked crossover study, patients were randomized 1:1 to BTFC-DTFC or DTFC-BTFC treatment sequences. Patients self-administered each medication for 7 days, with a 48-hour washout period between treatments, and rated ocular discomfort after each treatment period. Medication preferences based on ocular comfort (primary endpoint) and anticipated adherence were assessed. Safety outcomes included adverse events and intraocular pressure. Between-group differences in treatment preference and ocular discomfort scores were analyzed using chi-square and Wilcoxon-Mann-Whitney tests, respectively. Adherence, intraocular pressure, and adverse events were summarized descriptively.In total, 112 patients were enrolled (mean ± SD age, 66±11 years), and 109 patients completed the study. Numerically, more patients in the intent-to-treat dataset preferred BTFC versus DTFC (59.3% versus 40.7%); however, this result was not statistically significant (treatment difference, 18.6%; P=0.0670). Mean ocular discomfort scores (range, 0-9) were statistically significantly lower with BTFC versus DTFC (2.6 versus 3.7; P=0.0002, Wilcoxon- Mann-Whitney test). More patients who preferred BTFC over DTFC were confident that they would adhere to their preferred medication. Treatment-related adverse events included blurred vision with BTFC and eye irritation or eye pain with DTFC.BTFC and DTFC were preferred by approximately 60% and 40% of patients, respectively, and BTFC was associated with less patient-reported ocular discomfort. Greater ocular comfort of glaucoma medications may improve treatment adherence.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Current diagnostic and therapeutic decisions based on the outcomes of imaging technologies have become a common practice in every ophthalmic subspecialty. New devices and tools for evaluating the retina and optic nerve head, such as scanning laser polarimetry and spectral-domain optical coherence tomography (OCT), are widely used in clinical practice. These technologies provide objective quantitative measurements and in vivo real-time images of ocular structures. The performance of imaging devices is continuously being improved, and thus knowledge of their applications, advantages, and limitations must also be continuously updated to optimize their management by clinicians. While imaging technologies require relatively transparent media, the variability of the measurements acquired by these devices is low, making these instruments useful for monitoring changes over time. In this issue, M. Ara et al. report excellent reproducibility of scanning laser polarimetry in healthy and glaucoma patients. In their review article, J. J. Garcia-Medina et al. evaluated the effects of posterior capsule opacification and found that image quality improves after capsulotomy, but a new baseline for future comparisons should be established. Additionally, R. L. Brautaset et al. report that OCT allows for the acquisition of reliable macular measurements in individuals with moderate to severe keratoconus. M. Cavallari et al. developed a semiautomated, computer-based method to detect and quantify retinal vessel abnormalities by analyzing digital fundus photographs. This tool was successfully used to evaluate patients with hypertensive retinopathy and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. G. S. K. Yau et al. compared central macular thickness measured by OCT in Chinese children and found that it was thicker in myopic eyes compared to emmetropic and hyperopic eyes. Three papers regarding the role of the ganglion cell complex in different disorders, multiple sclerosis, age-related macular degeneration, and glaucoma, demonstrated that the same tool could be used with different approaches depending on the disease: “Comparative Diagnostic Accuracy of Ganglion Cell-Inner Plexiform and Retinal Nerve Fiber Layer Thickness Measures by Cirrus and Spectralis Optical Coherence Tomography in Relapsing-Remitting Multiple Sclerosis” by J. J. Gonzalez-Lopez et al.; “Can Variability of Pattern ERG Signal Help to Detect Retinal Ganglion Cells Dysfunction in Glaucomatous Eyes?” by A. Mavilio et al.; and “Ganglion Cell Complex Evaluation in Exudative Age-Related Macular Degeneration after Repeated Intravitreal Injections of Ranibizumab” by A. Perdicchi et al. J. J. Gonzalez-Lopez et al. observed a better sensitivity-specificity balance for the macular ganglion cell complex measured with OCT in relapsing-remitting multiple sclerosis than peripapillary retinal nerve fiber layer thickness, while A. Mavilio et al. found that reduction of the ganglion cell complex was related to reduced amplitude and increased variability of the phase of the steady-state pattern electroretinogram in glaucoma. On the other hand, A. Perdicchi et al. demonstrated that the loading phase for ranibizumab in aged-related macular degeneration had no toxic effects on the ganglion cell complex. R. Mastropasqua et al. and M. Di Nicola et al. provide reviews regarding advanced morphologic and functional magnetic resonance techniques in glaucoma and functional and structural abnormalities in deferoxamine retinopathy, respectively. Information concerning magnetic resonance imaging in glaucoma is limited and mostly based on mouse models and patients with advanced glaucoma. Nevertheless, some results support the potential for these techniques to detect early glaucomatous changes. M. Di Nicola et al. revealed that imaging technologies (color fundus photographs, autofluorescence, and OCT) may facilitate the management of deferoxamine retinopathy and their report highlights the need for guidelines to enhance the diagnosis and follow-up of these patients. A wide variety of image modalities and optic enhancements, including fundus autofluorescence, microperimetry, adaptive optics, or faster OCTs, recently emerged. Using different image modalities, clinicians can emphasize the features of a particular anatomic structure of a tissue. M. Bertolotto et al. evaluated various paracentral hyperautofluorescence retinal patterns and their relationship with changes in the retinal layers. Hyperautofluorescence was mainly related to a “window effect” rather than an accumulation of lipofuscin. Adaptive optics combined with OCT or fundus photography allow for high-resolution images due to the improvement in lateral resolution by correcting for aberrations in the eye. This technology reaches resolutions close to 2 to 4 µm, which is high enough to identify even cone photoreceptors. D. Supriya et al. report strong correlations between retinal sensitivity, evaluated by microperimetry, and the mean cone packing density at different macular eccentricities measured with an adaptive optics retinal camera. Further studies are required, however, to determine normative variations in cone structure-function correlation. OCT has changed many protocols and ways of managing different ocular diseases. Moreover, OCT has modified how clinicians look at the retina. The assessment of retinal abnormalities based on evaluation of every layer rather than the global thickness has advanced ophthalmology. Because images evaluated through OCT provide information of the actual retina anatomy, but not exactly the same information as obtained with histology; last year an international panel of experts in vitreoretinal diseases and imaging suggested a consensus nomenclature for the classification of retinal and choroidal layers and bands observed in OCT scans (IN•OCT consensus). P. Tortorella et al. evaluated the changes in two of these retinal layers, the photoreceptor inner segment ellipsoid band and the interdigitation zone, in eyes with uveitic macular edema. Interruption of these lines was related to poor visual acuity. R. L. M. Wong et al. report that the outer retinal layer thickness (distance between the external limiting membrane and retinal pigment epithelium) correlated better than total thickness with visual acuity in patients with diabetic macular edema. In summary, this issue includes different points of view presented by diverse authors covering several topics related to advances in imaging techniques for ophthalmic diseases. This publication will provide valuable information that should be helpful in clinical practice. Antonio Ferreras Michele Figus Paolo Frezzotti Michele Iester

Purpose. macular choroidal neovascularization (CNV) is one of the most vision-threatening complications of myopia, which can lead to severe vision loss. Our purpose was to evaluate the safety and efficacy of trans-corneal injection of ranibizumab in the treatment of myopic CNV in aphakic patients. Materials and Methods. ten eyes of 10 aphakic patients with CNV secondary to pathologic myopia treated with three trans- corneal injection of ranibizumab were evaluated. A complete ophthalmologic examination including best-corrected visual acuity (BCVA) and fundus biomicroscopy, specular microscopy, fundus optical coherence tomography (OCT), fluorescein an- giography (FA) were performed at baseline and monthly for all patients. Mean time of follow-up was 6 months. results. The mean axial length was 27,6 mm (range, 25.7-31.3 mm). The mean initial visual acuity (VA) was 0.19 (decimal equivalent). A statistically significant improvement to a mean VA of 0.33 decimal equivalent (log-MAR:0.48) was demon- strated at the final follow-up. VA improved by a mean of 2.86 lines. Mean central macular thickness (CMT) measured with OCT was 340 μm (range, 179-663 μm) at the baseline, and was reduced significantly at the final follow-up to 212μm (range, 125-455 μm). No injection complications or drug-related side effects were noted during the follow-up period. Conclusions. in this small series of aphakic eyes with limited follow-up, ranibizumab by anterior chamber administration seems to be a safe and effective treatment for CNV secondary to pathologic myopia (PM), without any complications. Further studies to evaluate the safety and efficacy are justified.

Abstract Purpose Central serous chorioretinopathy (CSCR) is a disease in which a serous detachment of the neurosensory retina occurs over an area of leakage from the choriocapillaris through the retinal pigment epithelium (RPE). CSCR can be acute or chronic. Classic image studies for CSCR are Fluorescine Angiography (FA) and Optical Coherence Tomography (OCT).No medical therapy is currently indicated for CSCR despite a range of potential medical treatments evaluated in many case reports. Argon laser photocoagulation can be considered only with a single leak located more than 300 µm from the center of the fovea. Autofluorescence (AF) with ultra‐widefield scanning laser and Subthreshold Micropulse (SDM) photostimulation with true yellow 577nm diode laser are the newer diagnostic and therapeutic options. Methods AF with ultra‐widefield scanning laser (Daytona™, Optos plc UK) was performed in fifteen patients affected by acute and chronic CSCR. All the areas of serous retinal detachment visible at AF as hyperfluorescence were treated with SDM photostimulation (IQ 577™ true yellow laser, Iridex CA). Controls were made at 15 days, 1 and three months after the treatment. Results Ultra‐widefield AF allowed to identify several zones of serous detachment not detected with FA and out of range of OCT scans. In most of cases we obtained the complete resolution of serous detachment and visual acuity improvement. Gain in visual acuity was better in acute cases of CSCR. Conclusion Ultra‐widefield AF followed by SDM photostimulation can be an effective diagnostic and therapeutic option for patients with acute and chronic CSCR.

Purpose. macular choroidal neovascularization (CNV) is one of the most vision-threatening complications of myopia, which can lead to severe vision loss. Our purpose was to evaluate the safety and efficacy of trans-corneal injection of ranibizumab in the treatment of myopic CNV in aphakic patients. Materials and Methods. ten eyes of 10 aphakic patients with CNV secondary to pathologic myopia treated with three trans- corneal injection of ranibizumab were evaluated. A complete ophthalmologic examination including best-corrected visual acuity (BCVA) and fundus biomicroscopy, specular microscopy, fundus optical coherence tomography (OCT), fluorescein an- giography (FA) were performed at baseline and monthly for all patients. Mean time of follow-up was 6 months. results. The mean axial length was 27,6 mm (range, 25.7-31.3 mm). The mean initial visual acuity (VA) was 0.19 (decimal equivalent). A statistically significant improvement to a mean VA of 0.33 decimal equivalent (log-MAR:0.48) was demon- strated at the final follow-up. VA improved by a mean of 2.86 lines. Mean central macular thickness (CMT) measured with OCT was 340 &mu;m (range, 179-663 &mu;m) at the baseline, and was reduced significantly at the final follow-up to 212&mu;m (range, 125-455 &mu;m). No injection complications or drug-related side effects were noted during the follow-up period. Conclusions. in this small series of aphakic eyes with limited follow-up, ranibizumab by anterior chamber administration seems to be a safe and effective treatment for CNV secondary to pathologic myopia (PM), without any complications. Further studies to evaluate the safety and efficacy are justified.

Scleral rupture due to bulb bursting can result from a heavy contusion. Owing to refined surgical techniques and the use of antibiotics and cortisone-based medication, more conservative concepts have followed. In major ruptures, the results were almost always very poor, with atrophy or subatrophy of the eyes.A 63-year-old man with major left ocular trauma and intraocular lens dislocation in the subconjunctival area was referred to the authors for clinical and surgical evaluation.Surgery was performed 3 weeks after the trauma to allow for improvement in the patient's condition. The reabsorption of a palpebral-frontal hematoma, which made bulb exploration almost impossible, was fundamental in order to proceed. After 1 year, the best-corrected visual acuity was 0.9. In fact, great improvements in surgical techniques in recent years have allowed us to consider the problem of major rupture in a new way, both technically and from an organizational point of view.In terms of organization, the concept of urgent surgical procedures must be reevaluated, because besides traumatic damage, incomplete surgical measures may result. This makes all treatment useless, in both barely equipped and highly specialized centers.