András Berta

Molecular mechanisms of retinal pigment epithelium damage and development of age‐related macular degeneration

Age‐related macular degeneration (AMD) is attributed to a complex interaction of genetic and environmental factors. It is characterized by degeneration involving the retinal photoreceptors, retinal pigment epithelium (RPE) and Bruch’s membrane, as well as alterations in choroidal capillaries. AMD pathogenesis is strongly associated with chronic oxidative stress and inflammation that ultimately lead to protein damage, aggregation and degeneration of RPE. Specific degenerative findings for AMD are accumulation of intracellular lysosomal lipofuscin and extracellular drusens. In this review, we discuss thoroughly RPE‐derived mechanisms in AMD pathology.

Multiple sclerosis-associated uveitis

Background/aims: To describe the clinical characteristics and course of 16 patients with uveitis associated with multiple sclerosis (MS). Methods: The records of 1254 patients with uveitis were reviewed. Sixteen of these patients had MS. The history, review of systems, ocular findings, and clinical test results of each of these 16 subjects were analyzed. The mean follow-up time was 38 months. Results: Most patients with MS-associated uveitis were white females between 20 and 50 years of age. The diagnosis of MS preceded the onset of uveitis in 56%, followed it in 25%, and was made concurrently in 19% of the cases. In 94%, the uveitis was bilateral. Pars planitis was the most frequent form of uveitis in our study population (81%); concomitant anterior chamber inflammation was common and was granulomatous in nature 56% of the time. Forty-one percent of the eyes with MS-associated uveitis had 20/30 or better initial visual acuity. Among these treated patients, significant loss of visual acuity was uncommon. Conclusions: MS-associated uveitis should be suspected in white female patients with bilateral uveitis, especially if pars planitis is present. These patients often retain useful vision for many years if treated.

Two-Year Safety and Efficacy of Ranibizumab 0.5 mg in Diabetic Macular Edema: Interim Analysis of the RESTORE Extension Study

OBJECTIVE To evaluate the 2-year safety and efficacy of ranibizumab 0.5 mg in diabetic macular edema (DME). DESIGN Twenty-four-month, open-label, multicenter, Phase IIIb extension study. PARTICIPANTS Two hundred forty of 303 patients with visual impairment due to DME who completed the RESTORE core study and entered the extension. METHODS All patients were eligible to receive ranibizumab 0.5 mg pro re nata (PRN) from month 12 (end of core study) to month 36 based on best-corrected visual acuity (BCVA) stability and disease progression retreatment criteria. Patients were also eligible to receive laser PRN according to Early Treatment Diabetic Retinopathy Study guidelines. A preplanned interim analysis was performed at month 24, stratifying by treatment groups as in the RESTORE core study and referred to as prior ranibizumab, ranibizumab plus laser, or laser groups in the extension. MAIN OUTCOME MEASURES Incidence of ocular and nonocular adverse events (AEs) and mean change in BCVA. RESULTS Two hundred twenty patients (92%) completed the month 24 visit. Over 2 years, the most frequent ocular serious AE (SAE) and AE were cataract (2.1%) and eye pain (14.6%), respectively. The main nonocular AEs were nasopharyngitis (18.8%) and hypertension (10.4%). There were no cases of endophthalmitis, and the incidences of nonocular SAEs were low. Of the patients entering the extension, 4 deaths were reported in the second year, none of which were related to study drug or procedure. Mean BCVA gain, central retinal thickness (CRT) decrease, and National Eye Institute Visual Functioning Questionnaire-25 (NEI VFQ-25) composite score observed at month 12 were maintained at month 24 (prior ranibizumab: +7.9 letters, -140.6 μm, and 5.6, respectively; prior ranibizumab plus laser: +6.7 letters, -133.0 μm, and 5.8, respectively), with an average of 3.9 (prior ranibizumab) and 3.5 ranibizumab injections (prior ranibizumab plus laser). In patients treated with laser alone in the core study, the mean BCVA, CRT, and NEI VFQ-25 composite score improved from month 12 to month 24 (+5.4 letters, -126.6 μm, and 4.3, respectively), with an average of 4.1 ranibizumab injections. CONCLUSIONS Ranibizumab 0.5 mg administered according to prespecified visual stability and disease progression criteria was well tolerated, with no new safety concerns identified over 2 years. Overall, an average of 3.8 ranibizumab injections was sufficient to maintain (prior ranibizumab) or improve (prior laser) BCVA, CRT, and NEI VFQ-25 outcomes through the second year. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Repeatability of ocular biomechanical data measurements with a scheimpflug-based noncontact device on normal corneas

PURPOSE To analyze the repeatability of a new device measuring ocular biomechanical properties, central corneal thickness (CCT), and intraocular pressure (IOP) and to investigate these parameters and their correlations in healthy eyes. METHODS Three consecutive measurements were performed on each eye using the CorVis ST device (Oculus Optikgeräte, Inc., Wetzler, Germany). Ten specific parameters, CCT, and IOP were measured. Biometric data were recorded with IOLMaster (Carl Zeiss Meditec, Jena, Germany). RESULTS This study comprised 75 eyes of 75 healthy volunteers (mean age: 61.24 ± 15.72 years). Mean IOP was 15.02 ± 2.90 mm Hg and mean CCT was 556.33 ± 33.13 μm. Intraclass correlation coefficient (ICC) was 0.865 for IOP and 0.970 for CCT, and coefficient of variation was 0.069 for IOP and 0.008 for CCT. ICC was 0.758 for maximum amplitude at highest concavity and 0.784 for first applanation time, and less than 0.6 for all other parameters. The device-specific data showed no significant relationship with age and axial length. Flattest and steepest keratometric values and IOP showed a significant correlation with the 10 device-specific parameters. CONCLUSIONS The CorVis ST showed high repeatability for only IOP and pachymetric values. Single measurements are not reliable for the 10 device-specific parameters. The device allows for conducting clinical examinations and screening for surgeries altering ocular biomechanical properties with some form of averaging of multiple measurements.

Stem cells of the adult cornea: from cytometric markers to therapeutic applications.

The cornea is a major protective shield of the interior of the eye and represents two thirds of its refractive power. It is made up of three tissue layers that have different developmental origins: the outer, epithelial layer develops from the ectoderm overlying the lens vesicle, whereas the stroma and the endothelium have mesenchymal origin. In the adult organism, the outermost corneal epithelium is the most exposed to environmental damage, and its constant renewal is assured by the epithelial stem cells that reside in the limbus, the circular border of the cornea. Cell turnover in the stromal layer is very slow and the endothelial cells probably do not reproduce in the adult organism. However, recent experimental evidence indicates that stem cells may be found in these layers. Damage to any of the corneal layers leads to loss of transparency and low vision. Corneal limbal stem cell deficiency results in severe ocular surface disease and its treatment by transplantating ex vivo expanded limbal epithelial cells is becoming widely accepted today. Stromal and endothelial stem cells are potential tools of tissue engineering and regenerative therapies of corneal ulcers and endothelial cell loss. In the past few years, intensive research has focused on corneal stem cells aiming to improve the outcomes of the current corneal stem cell transplantation techniques. This review summarizes the current state of knowledge on corneal epithelial, stromal and endothelial stem cells. Special emphasis is placed on the molecular markers that may help to identify these cells, and the recently revealed mechanisms that could maintain their “stemness” or drive their differentiation. The techniques for isolating and culturing/expanding these cells are also described.

Intravitreal Aflibercept for Macular Edema Secondary to Central Retinal Vein Occlusion: 18-Month Results of the Phase 3 GALILEO Study

PURPOSE To evaluate intravitreal aflibercept for treatment of macular edema secondary to central retinal vein occlusion (CRVO). DESIGN Randomized, double-masked, phase 3 study. METHODS A total of 177 patients with macular edema secondary to CRVO were randomized to receive 2 mg intravitreal aflibercept (n = 106) or sham (n = 71) every 4 weeks for 20 weeks. From weeks 24 to 48, patients were monitored every 4 weeks; the former group received intravitreal aflibercept as needed (PRN), and the sham group received sham. From weeks 52 to 76, patients were monitored every 8 weeks, and both groups received intravitreal aflibercept PRN. The primary endpoint (proportion of patients who gained ≥15 letters) was at week 24. This study reports exploratory outcomes at week 76. RESULTS The proportion of patients who gained ≥15 letters in the intravitreal aflibercept and sham groups was 60.2% vs 22.1% at week 24 (patients discontinued before week 24 were considered nonresponders; P < .0001), 60.2% vs 32.4% at week 52 (last observation carried forward, P < .001), and 57.3% vs 29.4% at week 76 (last observation carried forward; P < .001). Mean μm change from baseline central retinal thickness was -448.6 vs -169.3 at week 24 (P < .0001), -423.5 vs -219.3 at week 52 (P < .0001), and -389.4 vs -306.4 at week 76 (P = .1122). Over 76 weeks, the most common ocular serious adverse event in the intravitreal aflibercept group was macular edema (3.8%). CONCLUSIONS The visual and anatomic improvements seen after fixed, monthly dosing at week 24 were largely maintained when treatment intervals were extended. Patients with macular edema following CRVO benefited from early treatment with intravitreal aflibercept.

Reliability and repeatability of swept-source Fourier-domain optical coherence tomography and Scheimpflug imaging in keratoconus

PURPOSE: To evaluate the repeatability and reliability of a recently introduced swept‐source Fourier‐domain anterior segment optical coherence tomography (AS‐OCT) system and a high‐resolution Scheimpflug camera and to assess the agreement between the 2 instruments when measuring healthy eyes and eyes with keratoconus. SETTING: Department of Ophthalmology, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary. DESIGN: Evaluation of diagnostic test or technology. METHODS: Three consecutive series of anterior segment images were taken with AS‐OCT (Casia SS‐1000) followed by rotating Scheimpflug imaging (Pentacam high resolution). Axial keratometry in the steep and flat meridians and astigmatism values were recorded. Pachymetry in the apex, center, and the thinnest position and anterior chamber depth (ACD) measurements were also taken. RESULTS: This study enrolled 57 healthy volunteers (57 eyes) and 56 patients (84 eyes) with keratoconus. Significant difference was found in all measured anterior segment parameters between normal eyes and keratoconic eyes (P<.05). In keratoconic eyes, the difference between repeated measurements was less with AS‐OCT than with Scheimpflug imaging in every keratometry and astigmatism value, in apical thickness, and in ACD. For keratometry, the thinnest and central pachymetry measurement repeatability was better in healthy eyes than in keratoconic eyes with both instruments. In general, the mean difference between AS‐OCT and Scheimpflug imaging was higher in cases of keratoconus. CONCLUSIONS: Significant differences in keratometry, pachymetry, and ACD results were found between AS‐OCT and Scheimpflug imaging. However, the repeatability of the measurements was comparable. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned.

Evaluation of tear osmolarity in non-Sjögren and Sjögren syndrome dry eye patients with the tearlab system

Purpose: To evaluate tear osmolarity with the recently introduced TearLab system (TearLab Corporation, San Diego, CA) in patients with non-Sjögren syndrome dry eye (NSSDE) and Sjögren syndrome dry eye (SSDE), and in healthy subjects, and to compare the results with those from classical dry eye tests. Methods: Thirty-nine eyes of 21 patients with NSSDE, 39 eyes of 20 patients with SSDE, and 44 eyes of 22 healthy individuals were included in the study. Tear osmolarity was measured with the TearLab system, lid-parallel conjunctival folds score was examined with the slit lamp, and then the classical diagnostic tests such as Schirmer I test, tear film break-up time, and corneal staining were carried out, followed by the examination of meibomian glands and corneal transparency. Results: Mean tear osmolarity was 296.77 ± 16.48 mOsm/L in NSSDE (15% abnormal), 303.36 ± 17.22 mOsm/L in SSDE (23% abnormal), and 303.52 ± 12.92 mOsm/L in the control group (16% abnormal; P = 0.018, Kruskal–Wallis). Schirmer test, corneal staining, tear film break-up time, and meibomian gland status were significantly different in the 2 patient groups when compared with those in the control group (P < 0.0001). In the control and SSDE groups, no significant correlation was disclosed between tear osmolarity and any of the dry eye tests performed. Conclusions: Tear hyperosmolarity is considered a key factor that leads to dry eye symptoms and to the progression of clinical signs. Osmolarity measurements with the TearLab system disclosed no ability to distinguish between healthy individuals and patients with dry eye. This suggests that the TearLab device should not be used alone but in combination with classical dry eye tests.

Assessment and reproducibility of anterior chamber depth measurement with anterior segment optical coherence tomography compared with immersion ultrasonography

PURPOSE: To measure anterior chamber depth (ACD) with an anterior segment optical coherence tomography (AS‐OCT) and a standard ultrasonic (US) axial scan (A‐scan) device using an immersion technique and to assess repeatability, reproducibility, and correlations of the measurements. SETTING: Department of Ophthalmology, Medical Health and Science Center, University of Debrecen, Debrecen, Hungary. METHODS: Sixty healthy eyes of 41 patients were enrolled in a study. The central ACD was measured 5 times with AS‐OCT (Visante, Carl Zeiss Meditec) using its chamber tool and 5 times with a US A‐scan device (UltraScan Imaging System, Alcon Laboratories) using an immersion method. The measurements were performed consecutively by 2 independent observers. RESULTS: The mean ACD measured with AS‐OCT was 3.12 mm ± 0.33 (SD) by observer 1 and 3.11 ± 0.33 mm by observer 2 (P = .78). The repeatability was 0.8% ± 0.4% and 1.9% ± 1.4%, respectively. The reproducibility was 0.23%. The reliability coefficient with AS‐OCT was 99.6%. The mean ACD measured with immersion US A‐scan was 2.98 ± 0.33 mm by observer 1 and 2.95 ± 0.34 mm by observer 2 (P = .68). The repeatability was 6.4% ± 3.8% by observer 1 and 8.5% ± 4.9% by observer 2. The reproducibility was 0.88%. The reliability coefficient was 87.1% for US A‐scan measurements. The difference between ACD values with AS‐OCT and values with US A‐scan was statistically significant (P = .02). The correlation (r) between AS‐OCT and US A‐scan was 0.732 (P<.0001) by observer 1 and 0.802 (P<.0001) by observer 2. CONCLUSIONS: Anterior chamber measurements were significantly deeper with AS‐OCT than with US immersion A‐scan. Repeatability of ACD measurements was better with AS‐OCT than with immersion US, and reproducibility was equal with the 2 methods.

Anterior chamber depth measurements in phakic and pseudophakic eyes: Pentacam versus ultrasound device.

PURPOSE: To compare anterior chamber depth (ACD) measurements with a new optical device with those taken with a standard ultrasound (US) device in emmetropic phakic and pseudophakic eyes. SETTING: Department of Ophthalmology, Medical Health and Science Center, University of Debrecen, Debrecen, Hungary. METHODS: Forty‐two phakic and 42 pseudophakic patients with normal axial lengths (mean 22.91 mm ± 1.21 [SD]) were enrolled in the study. The ACD was measured 3 times with Scheimpflug‐based Pentacam (Oculus) and then 3 times with a standard A‐scan US device (AL‐2000, Tomey). The data were then analyzed. RESULTS: In the phakic group, the mean ACD was 2.87 ± 0.4 mm with the Pentacam and 2.89 ± 0.49 mm with ultrasound A‐scan (US) (P = .84). In the pseudophakic group, the mean ACD was 3.41 ± 0.28 mm and 3.97 ± 0.45 mm, respectively (P<.001). The correlation between measurements was significant in both the phakic and pseudophakic groups (r = .547/P<.001 and r = .404/P = .01, respectively). CONCLUSIONS: In phakic eyes, ACD measured with the Pentacam and with US was the same. However, in pseudophakic eyes, the difference was significantly lower when the ACD was measured with the Pentacam. Therefore, in pseudophakic patients, further evaluation of ACD data with the Scheimpflug‐based system is necessary.