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Purpose: To determine the best treatment for dissociated vertical deviation (DVD). Methods: The authors investigated the postoperative results of unilateral surgery for DVD in 14 patients when the visual acuity difference between the two eyes did not result in a postoperative dominance switch. All patients underwent bilateral medial rectus recession for congenital esotropia. Results: With this unilateral surgical procedure, all patients showed a significant improvement of the DVD in the primary position. None of the patients developed hypotropia, anti-elevation syndrome, or inferior oblique overaction in the contralateral (dominant) eye, and no changes were observed in the contralateral eye. Conclusions: Unilateral surgery for DVD in the non-dominant eye in case of strong fixation preference does not create a postoperative manifest DVD in the unoperated dominant eye. [ J Pediatr Ophthalmol Strabismus . 2022;59(1):60–64.]

To critically discuss the randomized clinical trials (RCTs) on glaucoma medical therapy for the management of pediatric glaucoma. RCTs on glaucoma drugs carried out on pediatric subjects with ocular hypertension and glaucoma were identified through systematic searches. The methods of the RCTs and the safety and the efficacy of the glaucoma drugs were reviewed and discussed. We included five RCTs. One study compared dorzolamide with 0.5% timolol gel; one brinzolamide with 0.5% levobetaxolol; one 0.25% betaxolol, 0.25% timolol gel, and 0.5% timolol gel; one latanoprost with 0.5% timolol; and one travoprost with 0.5% timolol. The primary outcome was safety for two studies and efficacy for three studies. None of the RCTs was powered to detect statistically significant differences in intraocular pressure (IOP) between treatments. In total, 658 subjects received at least one dose of study medication. Beta-blockers were administered to 359 patients, carbonic anhydrase inhibitor (CAI) to 154, and prostaglandins to 145 patients. IOP-lowering efficacy ranged from 20 to 23% for CAI, from 9 to 36% for beta-blockers, and from 26 to 27% for prostaglandins. The percentage of responders was 50% for CAI, ranged from 38 to 74% for beta-blockers and from 60 to 83% for prostaglandins. Two patients receiving timolol experienced a systemic, drug-related serious adverse event (one patient bradycardia and one pneumonia). Systemic, nonserious drug-related events occurred in 15 patients randomized to beta-blockers and in 8 patients randomized to CAI. No adverse events occurred in children treated with prostaglandins. RCTs that are available on medical therapy for glaucoma are few and underpowered. The proportion of responders is lower in children; however, in subjects who are responders, the efficacy of glaucoma drugs seemed to be comparable to that in adults. As systemic adverse events have been reported, including serious events with timolol, a particular attempt to minimize the absorption of the drug (using the lowest dose and the gel formulation of beta-blockers or considering the lacrimal punctum occlusion) and a follow-up that is more frequent and more focused on safety should be considered in pediatric subjects who are on topical glaucoma medications.

To describe and compare the conjunctival filtering bleb features after XEN gel implantation and trabeculectomy using anterior segment optical coherence tomography (AS-OCT) and in vivo confocal microscopy (IVCM). Fifty-two patients who underwent completely successful trabeculectomy (24 eyes) or completely successful XEN gel implantation (28 eyes) were consecutively enrolled. At the sixth-month follow-up, filtering blebs were analyzed with AS-OCT and IVCM. The main outcomes were the following: (i) bleb-wall epithelium cyst-like structure density and area (BECSD, BSCSA), (ii) bleb-wall sub-epithelium cyst-like structure density and area (BSCSD, BSCSA,), (iii) bleb-wall thickness (BT), (iv) bleb-wall epithelial thickness (BET), (v) bleb-wall reflectivity (BR), and (vi) bleb height (BH), for AS-OCT. Mean microcyst density (MMD) and area (MMA) and stromal meshwork reflectivity (SMR) were the IVCM outcomes. Six-month intraocular pressure was 11.46 ± 3.09 and 10.06 ± 3.39 mmHg in the XEN gel implantation and trabeculectomy, respectively (p > 0.05). At AS-OCT, XEN gel blebs showed lower BH, BT, BET, BR, (p

To assess and compare early changes in neuroinflammatory and vascular parameters in diabetic macular edema (DME) with subfoveal neuroretinal detachment (SND) after treatment with intravitreal dexamethasone (DEX-I) and ranibizumab (IVR). Thirty-three eyes (33 patients) with treatment naive DME with SND were retrospectively evaluated at baseline and 2 months after DEX-I (15 eyes) and 1 month after 3 monthly IVR injections (18 eyes). Inclusion criteria were: complete eye examination, good quality OCT and OCT-A images. OCT parameters included: central macular thickness (CMT); number of hyper-reflective retinal spots (HRS) in inner, outer (IR, OR) and full retina; choroidal thickness (CT), extent of disorganization of inner retinal layers (DRIL), outer retina integrity (OR). On OCT-A: foveal avascular zone (FAZ) parameters in the superficial capillary plexus (SCP); cysts area and perfusion density (PD) in SCP and deep capillary plexus (DCP) and flow voids (FV) in choriocapillaris. FAZ was analyzed using ImageJ, perfusion parameters and FV using MATLAB. BCVA increased equally after both treatments (13.0 ± 10.0 ETDRS letters, p

To compare intraocular pressure (IOP) measurements obtained with the Perkins applanation tonometer and Icare PRO (ICP) rebound tonometer in anesthetized aphakic or strabismus children. Furthermore, intra-operator correlation and inter-operator correlation have been evaluated, along with the effects of central corneal thickness (CCT) on IOP measurements. Seventy children undergoing examination under anesthesia with sevoflurane for aphakic patients and for surgery for strabismus were included. IOP have been measured twice immediately after anesthesia induction with both Perkins applanation tonometer (PAT) and ICP in one eye and by two different operators with both devices in the fellow eye. Furthermore, CCT was measured with ultrasound pachymetry Pacline (Optikon). Agreement between the device measurements has been evaluated using Bland–Altman analyses. Repeatability and reproducibility of the device have been evaluated with intraclass correlation coefficient (ICC) with a value > 0.75 associated with excellent reliability. The relationship between IOP and CCT has been evaluated with Spearman’s correlation coefficient r and determination coefficient r2. Mean difference in IOP measurements between ICP and PAT was 1.97 mmHg ± 1.23 mmHg (p

PURPOSE The aim of this study was to evaluate the safety and efficacy of tacrolimus 0.1% eye drops in a large population of pediatric patients affected by a severe form of vernal keratoconjunctivitis (VKC) who responded poorly to cyclosporine eye drops. METHODS This is a retrospective study based on standardized clinical charts and data collection of consecutive patients affected by severe VKC who responded poorly to cyclosporine eye drops topical treatment but treated with tacrolimus 0.1% eye drops with a follow-up of 18 months. Four clinical signs were graded for analysis: hyperemia, tarsal papillae, giant papillae, and limbal papillae. The blood tests for kidney and liver function and the tacrolimus level were studied. Visits were scheduled at baseline and at 3, 6, 12, and 18 months. Patients received tacrolimus 0.1% eye drops in both eyes 2 times daily. RESULTS Four hundred thirty-one patients were included. Three hundred twenty-five patients were affected by a seasonal form, whereas the remaining 106 by a perennial form. Statistical analysis on each single score showed a positive relevance (P < 0.001) from baseline to all other visits. No local or systemic complications were recorded. CONCLUSIONS Tacrolimus has been proposed as a treatment for severe forms of VKC. This study has confirmed the safety and efficacy of tacrolimus 0.1% eye drops in a large pediatric population of patients affected by a severe form of VKC who responded poorly to cyclosporine eye drops.

The role of the Tear Film and Ocular Surface Society (TFOS) Dry Eye Workshop (DEWS) II Diagnostic Methodology Subcommittee was 1) to identify tests used to diagnose and monitor dry eye disease (DED), 2) to identify those most appropriate to fulfil the definition of DED and its sub-classifications, 3) to propose the most appropriate order and technique to conduct these tests in a clinical setting, and 4) to provide a differential diagnosis for DED and distinguish conditions where DED is a comorbidity. Prior to diagnosis, it is important to exclude conditions that can mimic DED with the aid of triaging questions. Symptom screening with the DEQ-5 or OSDI confirms that a patient might have DED and triggers the conduct of diagnostic tests of (ideally non-invasive) breakup time, osmolarity and ocular surface staining with fluorescein and lissamine green (observing the cornea, conjunctiva and eyelid margin). Meibomian gland dysfunction, lipid thickness/dynamics and tear volume assessment and their severity allow sub-classification of DED (as predominantly evaporative or aqueous deficient) which informs the management of DED. Videos of these diagnostic and sub-classification techniques are available on the TFOS website. It is envisaged that the identification of the key tests to diagnose and monitor DED and its sub-classifications will inform future epidemiological studies and management clinical trials, improving comparability, and enabling identification of the sub-classification of DED in which different management strategies are most efficacious.

The clinical, scientific, economic, and regulatory impact of validated biomarkers and surrogate endpoints has the potential to revolutionize the approach to ocular surface diseases. At present, there is a growing interest in developing biomarkers for dry eye disease, and other ocular surface disorders and imaging are of the most promising approaches to this issue. Among the several and constantly evolving imaging technologies, some tools that are aimed to assess tear film stability and volume, meibomian gland morphology and function, and ocular surface microanatomy are now supported by a good body of evidence. To date, clinical trials on ocular surface diseases have slowly started incorporating imaging biomarkers for disease diagnosis and stratification and as surrogate endpoints. Major efforts are still needed, mainly aimed to improve automatic acquisition and quantitative analysis, standardization (standard operating procedures, normative databases etc.), and validation of imaging biomarkers.

To evaluate the efficacy and safety of atropine 0.01% in slowing myopia progression in European paediatric patients.Retrospective, medical records review study. Medical charts of paediatric patients with a myopia progression 0.5 D/year treated with atropine 0.01% for at least 1 year were included. Patients receive a complete ophthalmic examination before and 12 months after initiation of atropine treatment. A group of myopic untreated children serves as a control group. The rate of myopia progression at baseline and 12 months after treatment with atropine was evaluated. The rate of myopia progression in treated and untreated patients was also compared. Adverse events were recorded.Medical records of 52 treated and 50 control subjects were analysed. In the atropine group, the mean rate of myopia progression after 12 months of treatment (-0.54 ± 0.61 D) was significantly slower compared with the baseline progression (-1.20 ± 0.64 D; p 0.0001) and to the progression in the control group (-1.09 ± 0.64; p 0.0001). The responders patients were 41/52 (79%), whereas 11/52 patients (21%) showed a progression 0.50 D despite treatment. The only adverse event was temporary photophobia in five patients (9.6%), severe adverse events were not reported, and none of the patients discontinued the treatment.Low-dose atropine significantly slowed the rate of myopia progression in European paediatric patients with a favourable safety profile.

Objective: To assess the efficacy of “Yokoyama Procedure,” on non-highly myopic patients with acquired esotropia and hypotropia. Methods: The study involved 10 eyes of 5 patients with eso-hypotropia. Inclusion criteria were acquired esotropic-hypotropic strabismus with lateral rectus inferior displacement and superior rectus nasal displacement confirmed by magnetic resonance imaging, refractive errors between ±6 D, and axial length Results: Mean patient age was 64.8 ± 4.8 years. The mean globe axial length was 25.4 ± 0.76 mm and a mean corresponding spherical equivalent refraction of −3.7 ± 1.7 D was observed. Eight eyes on 10 had mild limitation in abduction, while the remaining 2 had no limitation. Three out of 10 eyes showed a moderate limited sursumduction, 5 eyes were categorized as mild, and the remaining 2 had no limitation. No evident post-operative limitation was present in any eye, in both abduction and sursumduction (p Conclusion: Yokoyama procedure is an effective, fast, reversible procedure to face eso-hypotropic acquired strabismus, even in patients with a clear magnetic resonance imaging displacement of superior and lateral rectus muscles, and absence of globe dislocation and of elevated myopia.

Optical coherence tomography angiography (OCT-A) has recently improved the ability to detect subclinical and early clinically visible microvascular changes occurring in patients with diabetes mellitus (DM). The aim of the present study is to evaluate and compare early quantitative changes of macular perfusion parameters in patients with DM without DR and with mild nonproliferative DR (NPDR) evaluated by two different swept-source (SS) OCT-A instruments using two scan protocols (3×3 mm and 6×6 mm). One hundred eleven subjects/eyes were prospectively evaluated: 18 healthy controls (control group), 73 eyes with DM but no DR (no-DR group), and 20 eyes with mild NPDR (DR group). All quantitative analyses were performed using ImageJ and included vessel and perfusion density, area and circularity index of the FAZ, and vascular complexity parameters. The agreement between methods was assessed according to the method of Bland-Altman. A significant decrease in the majority of the considered parameters was found in the DR group versus the controls with both instruments. The results of Bland-Altman analysis showed the presence of a systemic bias between the two instruments with PLEX Elite providing higher values for the majority of the tested parameters when considering 6×6 mm angiocubes and a less definite difference in 3×3 mm angiocubes. In conclusion, this study documents early microvascular changes occurring in the macular region of patients at initial stages of DR, confirmed with both SS OCT-A instruments. The fact that early microvascular alterations could not be detected with one instrument does not necessarily mean that these alterations are not actually present, but this could be an intrinsic limitation of the device itself. Further, larger longitudinal studies are needed to better understand microvascular damage at very early stages of diabetic retinal disease and to define the strengths and weaknesses of different OCT-A devices.

Purpose To evaluate with color fundus autofluorescence (FAF) different lesion components of macular neovascularization (MNV) secondary to age-related macular degeneration (AMD) and to assess its activity. Methods In total, 137 eyes (102 patients) with MNV underwent a complete eye examination, including color fundus photography, optical coherence tomography (OCT), OCT angiography, and confocal color FAF, with an excitation wavelength at 450 nm. Each image was imported into a custom-image analysis software for quantitative estimation of emission wavelength and green and red emission fluorescence (GEFC/REFC) intensity, considering both single components of neovascular AMD and different MNV types (type 1 and type 2 MNV, active and inactive MNV). Results Subretinal fluid (SRF) had significantly higher values of GEFC (P = 0.008 and P = 0.0004) and REFC intensity (P = 0.005 and P = 0.0003) versus fibrosis and atrophy. The emission wavelength from SRF was lower compared to atrophy (P = 0.024) but not to fibrosis (P = 0.46). No significant differences were detected between type 1 and 2 MNV. Considering active versus inactive MNVs, a difference was detected for all evaluated parameters (P < 0.001). Mean FAF wavelength of both MNV with SRF and intraretinal fluid (IRF) was lower versus inactive MNV (P < 0.001 and P = 0.005). MNV with SRF (P < 0.001) had higher values of GEFC and REFC versus inactive MNV (P < 0.001). MNV with IRF had higher values of GEFC versus inactive MNV (P = 0.05). Conclusions Quantitative color FAF can differentiate active versus inactive MNV, whereas no differences were found between type 1 and type 2 MNV. If these data can be further confirmed, color FAF may be useful for automatic detection of active MNV in AMD and as a guide for treatment. Translational Relevance Automatic quantitative evaluation of green and red emission components of FAF in AMD can help determine the activity of MNV and guide the treatment.

Purpose Scleral buckling (SB) is a surgical technique that has been used successfully to treat retinal detachments for the last 6 decades. The aim of this study was to report the long-term anatomical and functional outcomes of SB surgery in phakic patients with uncomplicated primary rhegmatogenous retinal detachment (PRRD). This article also outlines the benefits of SB compared to pars plana vitrectomy, such as reducing the risk of developing cataract, high intraocular pressure, and glaucoma, in addition to reducing surgical cost. Methods We retrospectively reviewed the clinical notes of 90 phakic eyes with PRRD treated with SB surgery that had a minimum of 5 years follow-up. Preoperative and postoperative characteristics were recorded. Main outcome measures were reattachment rate, best-corrected visual acuity (BCVA) improvement, and complications. Results A total of 90 eyes (88 patients) with phakic PRRD repaired through SB surgery were included. Mean age was 49.2 ± 14.6 years (range 20-80). Primary and final anatomic success was 96.7% and 100%, respectively. Mean preoperative BCVA was 0.3 ± 0.31 logMAR (6/12) and mean postoperative BCVA 0.1 ± 0.2 logMAR (pConclusions We report a high single operation success rate over time in phakic PRRD, repaired through SB surgery. Functional and anatomical success was maintained throughout the follow-up without complications. Therefore, the authors recommend the use of this technique in selected cases in order to reduce morbidity and the incidence of reoperations.

Purpose The aim of this study was to evaluate 1-year quantitative changes in specific inflammatory parameters on optical coherence tomography (OCT) / optical coherence tomography angiography (OCTA) in diabetic macular edema (DME) treated with subthreshold micropulse laser (SMPL). Methods Thirty-seven patients / eyes with previously treatment-naïve DME treated with SMPL were prospectively evaluated at 3, 6, and 12 months. Fifteen fellow eyes with only microaneurysms (MAS) not eligible for treatment were controls. Evaluated OCT / OCTA parameters included: central macular thickness (CMT); hyper-reflective retinal spots (HRS); disorganization of inner retinal layers (DRILs); MA in the superficial / deep capillary plexuses (SCP/DCP); cysts in the area at the SCP / DCP; and macular perfusion parameters (MATLAB, version 2017b). Results In the treated group, mean best corrected visual acuity (BCVA) progressively increased from 69.4 ± 12.0 to 76.0 ± 9.1 Early Treatment Diabetic Retinopathy Study (ETDRS) letters (P < 0.001) at 12 months; HRS decreased from baseline (80.75 ± 20.41) at 3 (73.81 ± 17.1, P = 0.002), 6 (69.16 ± 16.48, P < 0.0001), and 12 months (66.29 ± 18.53, P < 0.0001). MA decreased at 3 months in the DCP (P = 0.015), at 6 and 12 months in both plexuses (P ≤ 0.0007). BCVA, HRS, and MA remained stable in the controls during all follow-ups. DRIL was present in 18 of 37 patients at baseline and progressively decreased from 557.0 ± 238.7 to 387.1 ± 282.1 μm (P = 0.01). The area of cyst decreased both in the SCP (P = 0.03) and the DCP (P = 0.02). CMT and perfusion parameters did not change. Conclusions SMPL reduced the number of HRS (sign of activated microglia cells in the retina), MA, DRIL extension, and the area of cysts. Further studies are needed to confirm these preliminary data on the anti-inflammatory effect of SMPL, and to explore the mechanism of action. Translational Relevance The follow-up of OCT/OCTA noninvasive biomarkers offers a unique insight in the mechanism of laser action, suggesting an anti-inflammatory effect of SMPL.

To provide an overview of the pathogenic mechanisms underlying the correlation between ocular allergy and dry eye disease (DED), highlighting how the first condition may be a risk factor for the second one.Recent advances in our comprehension of the pathogenesis of ocular allergy and DED allow identifying several pathways of interaction between these two conditions. A growing body of evidence supports the role of ocular allergy as a risk factor for DED. Ocular allergy, particularly the severe forms of keratoconjunctivitis, can impact on different key mechanisms of the DED vicious cycle, including tear film instability, ocular surface inflammation and damage, and neurosensory abnormalities.Ocular allergy and DED are two common, relevant, symptomatic, not mutually exclusive conditions affecting the ocular surface. They share some clinical and biochemical features. To better understand the complex interactions between these two conditions, it's essential to consider the very wide spectrum of clinical conditions included in the term ocular allergy and the still largely unexplored peculiarities of the pediatric ocular surface physio-pathology and DED.

To review the state of the art of Accommodative Esotropia (AE) through careful study of what has been reported up to the point in literature. A literature search was done on PubMed using key words including “Accommodative esotropia”, “Infantile esotropia”, “Strabismus” and “Accommodation”. We systematically reviewed and critically appraised what has been written about AE and we tried to analyze that according to the current management of AE. Accommodative Esotropia (AE) is a form of strabismus characterized by convergent misalignment of the visual axes that can be associated with hyperopia and abnormal fusional divergence. Also abnormal accommodative convergence/accommodation ratio could be found. In lots of cases, AE initially presents as an intermittent esodeviation at age 1.5 to 4 years. The prevalence of AE has been estimated near 1-2% in the United States. The only treatment with an optical correction usually is successful in re-establishing alignment, but surgical correction is necessary in approximately 30% of cases.

Purpose The purpose of this study was to investigate the use of imaging biomarkers in published clinical trials (CTs) in ophthalmology and its eventual changes during the past 10 years. Methods We sampled from published CTs in the fields of cornea, retina, and glaucoma between 2005-2006 and 2015-2016. Data collected included year of publication, phase, subspecialty, location, compliance with Consolidated Standards for Reporting Trials, impact factor, presence and use of imaging biomarkers (diagnostic, prognostic and predictive; primary and secondary surrogate endpoints), and use of centralized reading centers. Results We included 652 articles for analysis, equally distributed in three timeframes (2005-2006, 2010-2011, and 2015-2016), mainly reporting phase IV CTs and trials on procedures (42.2% and 35.4%, respectively). Imaging biomarkers were included in 46.3% of the analyzed CTs and their use significantly increased over time (P < 0.05). Optical coherence tomography was the most frequently used device (27.7%), whereas diagnostic biomarkers and secondary surrogate endpoints were the most frequent biomarker types (19.5% and 22.5%, respectively). Early-phase CTs showed an increase in the use of biomarkers for patient selection and stratification over time (P < 0.05), but not in the use of imaging surrogate endpoints (P = 0.90). Only 3 of 59 (5.1%) of phase III CTs included primary surrogate imaging endpoints, whereas secondary surrogate imaging endpoints were present in 50.8% of these trials (P < 0.001). Retinal CTs had the highest prevalence for each type of imaging biomarker (P < 0.001). Reading centers were used in 52 of 302 CTs (17.2%), with no significant time-related increase. Conclusions Imaging biomarkers are increasingly used in published CTs in ophthalmology. Additional efforts, including centralized reading centers, are needed to improve their validation and use, allowing a wider use of these tools as primary surrogate endpoints in phase III CTs.

To report a novel spectral-domain optical coherence tomography (SD-OCT) finding in children affected by tilted disc syndrome (TDS), and to correlate it with early visual field defects. Patients between 5 and 17 years old with TDS were enrolled in this study. The diagnosis of TDS was made by stereoscopic fundus photography, when the upper edge of the optic disc protruded anteriorly relative to its lower edge. All eyes were examined with 12 radial SD-OCT B-scans of 12 mm centered on the optic disc; the fundus area encompassing the optic nerve was additionally scanned using several vertical and horizontal scans.. C-scan SD-OCT were acquired using the Macular Cube 512 x128 to create the en face image. Standard automated perimetry 24–2 tests were performed on all patients. Thirty-eight eyes of 20 pediatric patients with TDS syndrome were enrolled during this 24-months clinical trial. Their mean age was 10.9 ± 2.7 years (range 7–15 years), 12 (60%) were male and eight (40%) were female. The OCT images of the optic discs showed a protrusion of the upper edge of Bruch’s membrane and choroid at the nasal edge of the optic disc in 39.5% of the eyes. The retinal nerve fiber tissue appeared to be herniated into this protrusion and bent superiorly in 15 eyes. This severe bending corresponded to early visual field anomalies that were not reduced by corrective lenses in 46.7% of the eyes. Visual field defects that do not improve by increased myopic correction in TDS may be due to the severe bending of the retinal nerve fiber tissue, which would impair axonal flow.

To evaluate the efficacy and safety of bimatoprost plus timolol fixed combination (BTFC) in patients with primary open angle glaucoma (POAG) previously treated with dorzolamide plus timolol fixed combination (DTFC).Retrospective, medical records review study. Medical records of patients with POAG previously treated with DTFC and then switched to BTFC for poor intraocular pressure (IOP) control or ocular discomfort were included in the analysis. One baseline IOP diurnal curve, and one diurnal curve under each treatment were required to be eligible for this study. The primary outcome was to compare the mean diurnal IOP between DTFC and BTFC. Secondary outcomes were to compare the IOP diurnal fluctuation, and the percentage of patients achieving a target IOP14,16, and18 mmHg between the two treatments.Medical records of 96 patients were analyzed (mean age 65.8 years ± 7.2, range 39-89 years). The mean diurnal IOP was 23.7 ± 3.8 mmHg at baseline, 16.9 ± 3.4 mmHg with DTFC and 15.1 ± 2.9 mmHg after therapy was switched to BTFC (p0.0001 each treatment vs baseline; p0.0001 DTFC vs BTFC). The proportion of patients achieving a mean diurnal IOP18,16, and14 mmHg was 76%, 35.4%, and 12.5% with DTFC and 81.2%, 68.8%, and 37.5% with BTFC (p = 0.20, p0.01, and p0.0001 between the two treatments, respectively). IOP fluctuation did not differ significantly between the treatments.BTFC can provide additional lowering in the mean diurnal IOP in patients previously treated with DTFC with no significant differences in the safety and tolerability profile.

To study visual and anatomical outcomes of sequenced combined therapy using intravitreal bevacizumab followed by photodynamic therapy (PDT) in eyes with retinal angiomatous proliferation (RAP). Safety and rate of intravitreal injections were also evaluated.We conducted a prospective non-comparative pilot study of consecutive patients newly diagnosed with RAP. PDT guided by indocyanine green (ICG) angiography was applied 8+/-2 days after the intravitreal bevacizumab (1.25 mg) injection. At baseline and every month after the injection, best-corrected visual acuity (BCVA) measurement, complete eye examination including dynamic fluorescein and ICG angiography, and optical coherence tomography (OCT) were performed.In all, 21 eyes of 18 patients with RAP were enrolled. The mean age was 77 (range 65-86) years. Mean visual acuity at baseline was 0.63+/-0.25 logMAR. After treatment BCVA showed no statistically significant differences between each visit (P=0.10, ANOVA). At 9 months, the BCVA improved by three or more lines in three eyes (14%), remained stable in twelve eyes (57%), and worsened in six eyes (29%). Foveal thickness decreased significantly between baseline and all the follow-up visits (P0.01, ANOVA). A total of 36 intravitreal injections were given during the study with a mean of 1.7 injections per eye (range 1-3 injections per eye). No ocular or systemic adverse events were reported.A possible synergistic effect may arise from the combination of intravitreal bevacizumab with PDT for the treatment of RAP. These findings also suggest a possible benefit of combo therapy in the rate of intravitreal re-injections.

To evaluate, by in vivo laser scanning confocal microscopy (LSCM), the corneal findings in moderate-to-severe dry eye patients before and after treatment with topical corticosteroid and to associate the confocal findings to the clinical response.Fifty eyes of 50 patients with moderate-to-severe dry eye were included in this open-label, masked study. Exclusion criteria were any systemic or ocular condition (other than dry eye) and any systemic or topical treatment (except artificial tears), ongoing or performed in the previous 3 months, with known effect on the ocular surface. All patients were treated with loteprednol etabonate ophthalmic suspension 0.5% qid for 4 weeks. Baseline and follow-up (day 30 ± 2) visits included Ocular Surface Disease Index (OSDI) questionnaire, full eye examination, and central cornea LSCM. We compared data obtained before and after treatment and looked for associations between baseline data and steroid-induced changes. Based on the previously validated OSDI Minimal Clinically Important Difference, we reanalyzed the baseline findings comparing those patients clinically improved after steroids to patients not clinically improved after steroids.Ocular Surface Disease Index score and LSCM dendritic cell density (DCD) significantly decreased after treatment. Baseline DCD correlated with both OSDI and DCD steroid-related changes (r = -0.44, p0.05 and r = -0.70, p0.01, respectively; Spearman) and was significantly higher in patients clinically improved after steroids than in patients not clinically improved after steroids (164.1 ± 109.2 vs. 72.4 ± 45.5 cells/mm2, p0.01; independent samples t test).Laser scanning confocal microscopy examination of DCD allows detection of treatment-related inflammation changes and shows previously unknown associations between confocal finding and symptoms improvement after treatment. These promising preliminary data suggest the need for future studies testing the predictive value of DCD for a clinical response to topical corticosteroids.

Purpose: To describe macular lesions in patients with deferoxamine (DFO) retinopathy, and to follow their clinical course using multimodal imaging. Methods: The authors retrospectively reviewed charts and multimodal imaging of 20 patients with β-thalassemia diagnosed with DFO retinopathy (40 eyes) after a minimum of 10 years of DFO treatment. Imaging included fundus photography, near-infrared reflectance and fundus autofluorescence imaging on confocal laser scanning ophthalmoscope, and spectral domain optical coherence tomography. Results: Mean age of the 20 patients was 45 years, and mean duration of subcutaneous DFO therapy was 32 years (range, 20–52 years). Ten patients (50%) showed different types of pattern dystrophy–like fundus changes, including butterfly shaped–like (n = 3), fundus flavimaculatus–like (n = 3), fundus pulverulentus–like (n = 3), and vitelliform-like (n = 1) changes. Ten patients (50%) presented only minimal changes in the macula; these patients were significantly younger than patients presenting other patterns (P = 0.023). Confocal laser scanning ophthalmoscope and spectral domain optical coherence tomography showed that these abnormalities were more diverse and widespread than expected by ophthalmoscopy. Abnormal fundus autofluorescence and/or near-infrared reflectance signals corresponded to accumulation of material located within the outer retina or in the Bruch membrane–retinal pigment epithelium (RPE) complex on spectral domain optical coherence tomography. Follow-up examinations during a 40-month period revealed progressive development of RPE atrophy in areas of pattern dystrophy–like changes. Conclusion: DFO retinopathy included a variety of pattern dystrophy–like changes or minimal changes affecting the RPE–Bruch membrane–photoreceptor complex. Multimodal imaging demonstrated that fundus changes were more diverse and widespread than expected from ophthalmoscopy. Consistently with previous histologic description of DFO retinopathy, multimodal imaging confirmed that photoreceptor outer-derived retinoids, various fluorophores, and RPE displacement or clumping are involved in DFO retinopathy, finally leading to frank RPE atrophy in most cases of pattern dystrophy–like changes.

In vivo confocal microscopy (IVCM) is an emerging technology that provides minimally invasive, high resolution, steady-state assessment of the ocular surface at the cellular level. Several challenges still remain but, at present, IVCM may be considered a promising technique for clinical diagnosis and management. This minireview summarizes some key findings in IVCM of the ocular surface, focusing on recent and promising attempts to move ‘‘from bench to bedside’’. IVCM allows prompt diagnosis, disease course follow-up, and management of potentially blinding atypical forms of infectious processes, such as acanthamoeba and fungal keratitis. This technology has improved our knowledge of corneal alterations and some of the processes that affect the visual outcome after lamellar keratoplasty and excimer keratorefractive surgery. In dry eye disease, IVCM has provided new information on the whole-ocular surface morphofunctional unit. It has also improved understanding of pathophysiologic mechanisms and helped in the assessment of prognosis and treatment. IVCM is particularly useful in the study of corneal nerves, enabling description of the morphology, density, and disease- or surgically induced alterations of nerves, particularly the subbasal nerve plexus. In glaucoma, IVCM constitutes an important aid to evaluate filtering blebs, to better understand the conjunctival wound healing process, and to assess corneal changes induced by topical antiglaucoma medications and their preservatives. IVCM has significantly enhanced our understanding of the ocular response to contact lens wear. It has provided new perspectives at a cellular level on a wide range of contact lens complications, revealing findings that were not previously possible to image in the living human eye. The final section of this mini-review provides a focus on advances in confocal microscopy imaging. These include 2D wide-field mapping, 3D reconstruction of the cornea and automated image analysis.

To summarize recent studies on in-vivo confocal microscopy (IVCM) findings in ocular allergy and dry eye disease (DED), highlighting the role of IVCM in the advancement of knowledge of these diseases.IVCM provided new data on ocular surface changes in both ocular allergy and DED. Corneal and conjunctival epithelial and inflammatory cells, corneal nerves, and Meibomian glands showed peculiar patterns of abnormalities, not easily discernable with current clinical exams in these two diseases and their subtypes. At present, small sample size of researches, and poor standardization and evidence of image analysis and interpretation are the most challenging issues.Ocular allergy and DED are common and increasing healthcare problems, and need better understanding of pathogenesis and natural history, more reliable endpoints, and more tailored diagnostic and therapeutic approaches. IVCM allows quick, noninvasive, steady-state respectful examination of the ocular surface at cellular level to be performed and has potential to be used in the future as a biomarker and to contribute to optimize the tailored management of these diseases.

Purpose. To study, by a new, integrated, laser scanning confocal microscopy approach, the ocular surface morpho-functional unit in patients with primary Sjogren syndrome (SSI), nonYSjogren syndrome dry eye (non-SSDE), and meibomian gland disease (MGD). Methods. Patients and age- and sex-matched control subjects (N = 60; 15 each) were consecutively enrolled in a prospective case-control study. Laser scanning confocal microscopy was used to obtain simultaneous optical sampling of the ocular surface components: cornea, bulbar and tarsal conjunctiva, MGs, and eyelid margin. Results. For all superficial epithelia, except eyelid margins, there were reduced cell densities in each group compared with that in controls (p G 0.001). The lowest cell densities were in the SSI group (p G 0.001). Eyelid margin superficial cell density was decreased only in MGD (p G 0.001). Basal epithelial cell density at the corneal apex was increased in both SSI and nonSSDE compared with that in controls (p G 0.01). In the conjunctiva, it was decreased in each group compared with that in controls (p G 0.01). Subbasal dendritic cell density was significantly increased in both SSI and MGD compared with that in controls (p G 0.01). Conjunctival inflammatory cell density and MG inflammation were increased in each group compared with those in controls (pG 0.001), with the highest values in SSI. Subbasal nerve plexi had fewer fibers and higher bead density in each group compared with those in controls (p G 0.001). There was increased tortuosity in both SSI and MGD (p G 0.001). Patients with MGD had the lowest MG acinar density, the largest diameter of acini and acinar orifices, and the highest secretion reflectivity (p G 0.001). Conclusions. Laser scanning confocal microscopy can provide an in vivo, noninvasive, high-resolution overview of the ocular surface morpho-funcional unit. This confocal integrated approach may be useful in both research and clinical settings. (Optom Vis Sci 2013;90:576Y586)

The purpose of this research was to study ocular surface inflammation in relation to systemic disease activity in rheumatoid arthritis (RA) patients with or without secondary Sjögren’s syndrome (SSII and non-SSII respectively). The study was conducted in two phases. In phase I, 12 patients with active RA SSII and 12 with active RA non-SSII were consecutively enrolled. Each completed an Ocular Surface Disease Index (OSDI) questionnaire and underwent a full eye exam and in vivo confocal microscopy examination of the cornea. Tear fluid samples were collected in sponges and analyzed for IL-1α, -6, and -8, and TNF-α. When RA activity was suppressed by systemic treatment the patients entered phase II of the study in which all of the phase I examinations were repeated. In RA SSII patients, OSDI, fluorescein staining dendritic cell density, and concentrations of IL-1α and IL-6 decreased significantly ( P

PURPOSE To study clinical and in vivo laser scanning confocal microscopy (LSCM) ocular surface findings in stable, medically controlled primary open-angle glaucoma (MCPOAG) patients. METHODS We recruited 100 consecutive patients with MCPOAG and 50 healthy controls. Patients had to have been treated with the same medical regimen without variation for the 18 months before enrollment and were excluded if there was a history of dry eye prior to glaucoma diagnosis. Each participant underwent ocular surface clinical and LSCM examination. RESULTS In MCPOAG patients, subbasal nerve length and tortuosity and dendritic cell density were increased compared to controls (P < 0.01), but there were no clinical abnormalities. Patients treated with preserved drugs (n = 80) had reduced tear film breakup time (P < 0.05, ANOVA), and those preserved with benzalkonium chloride (n = 72) had reduced Schirmer test values (P < 0.001). Patients (n = 50) treated with two or more drugs had increased lissamine green conjunctival staining (P < 0.001, LSD post hoc test). Patients (n = 29) treated with three or more eye drops daily had decreased Schirmer test values. Laser scanning confocal microscopy showed subbasal changes related to preservatives, type and number of drugs, and number of eye drops. CONCLUSIONS In stable MCPOAG patients without dry eye history, the ocular surface changes due to antiglaucoma medications are mostly subclinical. Active ingredients, preservatives, number of concomitant drugs, and number of eye drops instilled per day are all elements that can induce ocular surface changes. The clinical relevance of these changes remains to be determined.

Objective To investigate in a large sample of consecutive patients with neurofibromatosis type 1 (NF1) the possibility of including the presence of choroidal abnormalities detected by near-infrared reflectance (NIR) as a new diagnostic criterion for NF1. Design Cross-sectional evaluation of a diagnostic test. Participants and Controls Ninety-five consecutive adult and pediatric patients (190 eyes) with NF1, diagnosed based on the National Institutes of Health (NIH) criteria. Controls included 100 healthy age- and gender-matched control subjects. Methods Confocal scanning laser ophthalmoscopy was performed for each subject, investigating the presence and the number of choroidal abnormalities. Main Outcome Measures Sensitivity, specificity, and diagnostic accuracy for the different cutoff values of the criterion choroidal nodules detected by NIR compared with the NIH criteria. Results Choroidal nodules detected by NIR imaging were present in 79 (82%) of 95 of the NF1 patients, including 15 (71%) of the 21 NF1 pediatric patients. Similar abnormalities were present in 7 (7%) of 100 healthy subjects, including 2 (8%) of the 25 healthy pediatric subjects. The highest accuracy was obtained at the cutoff value of 1.5 choroidal nodules detected by NIR imagery. Sensitivity and specificity of the examination at the optimal cutoff point were 83% and 96%, respectively. Diagnostic accuracy was 90% in the overall population and 83% in the pediatric population. Both of these values were in line with the most common NIH diagnostic criteria. Conclusions Choroidal abnormalities appearing as bright patchy nodules detected by NIR imaging frequently occurred in NF1 patients. The present study shows that NIR examination to detect choroidal involvement should be considered as a new diagnostic criterion for NF1. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Recent success in clinical trials supports the use of adeno-associated viral (AAV) vectors for gene therapy of retinal diseases caused by defects in the retinal pigment epithelium (RPE). In contrast, evidence of the efficacy of AAV-mediated gene transfer to retinal photoreceptors, the major site of inherited retinal diseases, is less robust. In addition, although AAV-mediated RPE transduction appears efficient, independently of the serotype used and species treated, AAV-mediated photoreceptor gene transfer has not been systematically investigated thus so far in large animal models, which also may allow identifying relevant species-specific differences in AAV-mediated retinal transduction. In the present study, we used the porcine retina, which has a high cone/rod ratio. This feature allows to properly evaluate both cone and rod photoreceptors transduction and compare the transduction characteristics of AAV2/5 and 2/8, the two most efficient AAV vector serotypes for photoreceptor targeting. Here we show that AAV2/5 and 2/8 transduces both RPE and photoreceptors. AAV2/8 infects and transduces photoreceptor more efficiently than AAV2/5, similarly to what we have observed in the murine retina. The use of the photoreceptor-specific rhodopsin promoter restricts transgene expression to porcine rods and cones, and results in photoreceptor transduction levels similar to those obtained with the ubiquitous promoters tested. Finally, immunological, toxicological and biodistribution studies support the safety of AAV subretinal administration to the large porcine retina. The data presented here on AAV-mediated transduction of the cone-enriched porcine retina may affect the development of gene-based therapies for rare and common severe photoreceptor diseases. © 2011 Macmillan Publishers Limited All rights reserved. Recent success in clinical trials supports the use of adeno-associated viral (AAV) vectors for gene therapy of retinal diseases caused by defects in the retinal pigment epithelium (RPE). In contrast, evidence of the efficacy of AAV-mediated gene transfer to retinal photoreceptors, the major site of inherited retinal diseases, is less robust. In addition, although AAV-mediated RPE transduction appears efficient, independently of the serotype used and species treated, AAV-mediated photoreceptor gene transfer has not been systematically investigated thus so far in large animal models, which also may allow identifying relevant species-specific differences in AAV-mediated retinal transduction. In the present study, we used the porcine retina, which has a high cone/rod ratio. This feature allows to properly evaluate both cone and rod photoreceptors transduction and compare the transduction characteristics of AAV2/5 and 2/8, the two most efficient AAV vector serotypes for photoreceptor targeting. Here we show that AAV2/5 and 2/8 transduces both RPE and photoreceptors. AAV2/8 infects and transduces photoreceptor more efficiently than AAV2/5, similarly to what we have observed in the murine retina. The use of the photoreceptor-specific rhodopsin promoter restricts transgene expression to porcine rods and cones, and results in photoreceptor transduction levels similar to those obtained with the ubiquitous promoters tested. Finally, immunological, toxicological and biodistribution studies support the safety of AAV subretinal administration to the large porcine retina. The data presented here on AAV-mediated transduction of the cone-enriched porcine retina may affect the development of gene-based therapies for rare and common severe photoreceptor diseases. Gene Therapy (2011) 18, 637-645; doi:10.1038/gt.2011.3; published online 17 March 2011

PURPOSE. To study the clinical involvement of the ocular surface and the in vivo morphology of corneal cells and nerves, in patients affected by active and inactive Graves’ orbitopathy (GO). METHODS. The study included 26 consecutive GO patients and 20 age- and sex-matched healthy control subjects. GO was diagnosed on the basis of the criteria of the European Group on Graves’ Orbitopathy, and disease activity was evaluated by the Clinical Activity Score (CAS). Each participant underwent a full eye examination, including an evaluation of symptoms (Ocular Surface Disease Index score), tear break-up time, fluorescein and lissamine green staining, corneal apex sensitivity, and Schirmer’s test. The corneal apex was examined by means of confocal microscopy to investigate the number and morphology of epithelial and stromal corneal cells and subbasal nerves. RESULTS. Eleven (43%) of the 26 patients had active GO. Oneway ANOVA with the least-significant difference (LSD) post hoc test revealed statistically significant differences between patients and controls in all the evaluated parameters, except corneal sensitivity and nerve reflectivity. Among the GO patients, the only significant difference observed in active compared with inactive disease was in the number of hyperreflective (activated) keratocytes (P 0.001, LSD). Corneal sensitivity correlated inversely with proptosis (P 0.001, Spearman’s test). CONCLUSIONS. GO patients show clinical and confocal corneal alterations and signs and symptoms partially related to dry eye disease. The ocular surface inflammation in GO seems to be due to both the dry eye and the autoimmune orbitopathy. (Invest Ophthalmol Vis Sci. 2010;51:4574 – 4578) DOI

Background Macular edema is a known complication even after uneventful cataract surgery. The chronic use of prostaglandin analogs is a risk factor for the development of pseudophakic cystoid macular edema (CME). Nonsteroidal anti-inflammatory drugs (NSAIDs) are considered first-line therapy but refractory postsurgical CME represents a therapeutic challenge, as there is not an evidence-based treatment. Objective To report the use of a single implant of intravitreal dexamethasone for tafluprost-associated pseudophakic CME refractory to NSAIDs and to sub-Tenon's corticosteroid injections. Case report A 64-year-old female with ocular hypertension treated with tafluprost experienced decreased vision (visual acuity 20/60) and metamorphopsia 2 months after uneventful cataract extraction. Spectral domain optical coherence tomography (SD-OCT) revealed CME. After 1 month of topical and oral NSAIDs, CME was still evident on SD-OCT (visual acuity 20/50). Two sub-Tenon's betamethasone injections were performed at a 2-week interval. As CME was still present, 2 months after the diagnosis of CME (visual acuity 20/40), the patient underwent a single dexamethasone intravitreal implant. One month later, macular appearance was normal, and visual acuity increased to 20/30. This result was maintained throughout the 6 months of follow-up. Conclusion In this report, a single implant of intravitreal dexamethasone successfully treated pseudophakic CME associated with the use of prostaglandin analogs unresponsive to NSAIDs and sub-Tenon's betamethasone. The results of this report need to be corroborated by powered, prospective, randomized trials. The need for repeated treatments as well as the retreatment interval in patients requiring more than a single injection are issues still needing further investigations.

The authors recently observed a boy with bilateral choroidal neovascularization associated with Best's disease and compared the outcome of photodynamic therapy in one eye with the natural history of the untreated fellow eye. The final outcome of photodynamic therapy was inactive choroidal neovascularization, which seemed to be enveloped by the retinal pigment epithelium. The final appearance of the treated lesion was similar to the natural evolution of choroidal neovascularization in the untreated fellow eye. [J Pediatr Ophthalmol Strabismus 2010;47:121–122.]