In Vivo Confocal Microscopy Characterization of Candida parapsilosis Keratitis.

ABSTRACT: The present clinical case concerns two patients with mycotic keratitis because of Candida parapsilosis in which corneal confocal microscopy presented a characteristic feature of this pathogen. Both described patients used a therapeutic contact lens and administered a therapy with steroid eye drops which are well known predisposing factors for the onset of corneal mycoses. This report can be useful for correctly identifying the pathologic condition and quickly directing the therapy.

Aflibercept, ranibizumab and bevacizumab upcoming biosimilars: a general overview.

Anti-vascular endothelial growth factors currently are the first-line treatment option for neovascular age-related macular degeneration (nAMD) and other retinal vascular disorders, and their clinical use is associated with high financial burden. Biosimilars are a type of biological product highly similar to referral biologic drugs; they are increasing competition among biologics and have the potential to reduce the overall expenditures on biologics. In this comprehensive literature review, the current investigational biosimilars acting on retinal diseases are discussed. The authors review the results of clinical studies and highlight ongoing trials. Several biosimilar candidates are under evaluation and the pipeline will rapidly change in the future, as soon as each patent expires. Clinicians have to know these new therapeutic agents, which might come in the mainstream clinical practice as a more cost-efficient option.

Razumab -- the role of biosimilars for the treatment of retinal diseases.

Biologics targeting vascular endothelial growth factor (anti-VEGF) are the mainstay treatment of many vascular retinal pathologies. To date, Razumab is the only approved biosimilar for ophthalmic use. Razumab showed no differences compared to the innovator ranibizumab, in terms of VEGF binding activity nor in inhibition of VEGF-induced proliferation. Clinical and preclinical studies have shown a favorable efficacy and safety profile of Razumab. Nonetheless, even if clinical equivalence is expected, randomized controlled clinical trials are needed to directly compare Razumab with the innovator ranibizumab in different retinal diseases.

An update on ripasudil for the treatment of glaucoma and ocular hypertension.

Ripasudil (K-115) is a novel Rho-associated protein kinase (ROCK) inhibitor. The Rho-ROCK pathway regulates key downstream effectors involved in many cellular functions, in particular in the actin cytoskeleton activity. The clinical effects of ripasudil expected on the eye include an intraocular pressure-lowering effect and a wound-healing activity on corneal endothelial cells, but many other functions are currently under investigation. To date, ripasudil has been approved in Japan (2014) for the treatment of glaucoma and ocular hypertension, and several clinical trials are currently investigating its role in the treatment of Fuchs' corneal dystrophy. In this review, we will discuss its pharmacokinetics, pharmacodynamics and clinical efficacy, focusing also on its safety and tolerability profile.

An update on conbercept to treat wet age-related macular degeneration.

Wet age-related macular degeneration (w-AMD) represents the main cause of vision loss in the elderly in the western countries. The important role displayed by vascular endothelial growth factor (VEGF) in the pathogenesis of this disease has been largely demonstrated. For this reason, anti-VEGF drugs have been developed and currently are considered as the first-line treatment options in the management of w-AMD. Among the novel anti-VEGF agents studied, conbercept is a fusion protein composed of the combination between VEGF receptor domains with the Fc fragment of human immunoglobulin. It was already approved in China in 2014 for treating w-AMD. In this regard, the phase III PHOENIX trial has reported a good clinical efficacy and safety profile of conbercept for w-AMD, also by adopting a quarterly regimen. In this review, we will discuss its pharmacokinetics, pharmacodynamics, clinical efficacy, without neglecting also its safety and tolerability profile.

Omidenepag isopropyl for the treatment of glaucoma and ocular hypertension.

Glaucoma is a main cause of irreversible vision impairment and its prevalence is expected to rise significantly in the near future. Among the current medications, prostaglandin analogues (PGAs) are widely used and considered as a first-line strategy in the management of glaucoma and ocular hypertension (OHT). However, given the non-negligible incidence of adverse ocular effects (conjunctival hyperemia, increase of iris pigmentation and eyelash changes) due to the use of this class of drugs, novel PGAs are being investigated. Omidenepag isopropyl is a selective prostaglandin EP2 receptor agonist which was approved on September 21, 2018, in Japan for the treatment of glaucoma and OHT. In this review, we will discuss its pharmacokinetics, pharmacodynamics and clinical efficacy, focusing also on its safety and tolerability profile.

High-intensity focused ultrasound treatment in patients with refractory glaucoma.

PURPOSE: To assess the safety and efficacy of ultrasound coagulation of the ciliary body in refractory glaucoma. METHODS: This prospective multicenter interventional study was conducted in two Italian university-affiliated glaucoma centers: St. Orsola-Malpighi Teaching Hospital (Bologna, Italy) and University Eye Clinic of Genoa (Genoa, Italy). The main inclusion criterion was the diagnosis of glaucoma with a baseline intraocular pressure (IOP) ≥ 21 mmHg while on maximum topical and systemic medical hypotensive treatment. The EyeOP1 device (Eye Tech Care, Rillieux-la-Pape, France), which was employed in the study, uses miniaturized transducers to produce high-intensity focused ultrasound (HIFU). Treatment consisted of the sequential activation of each transducer lasting 4 s (group 1), 6 s (group 2) or 8 s (group 3). Hypotensive medications were interrupted after surgery and then prescribed only if postoperative IOP was ≥ 21 mmHg during follow-up visits. Patients were assessed before and 1, 7, 14, 30, 90 and 180 days after the procedure. Primary outcomes were the mean IOP reduction in the overall population and in groups 1, 2 and 3, and the rates of complete success, qualified success and failure. RESULTS: Thirty eyes (16 open-angle, 10 angle-closure and 4 neovascular glaucoma) of 30 patients were included. The mean preoperative IOP was 30.1 ± 10.5 mmHg. Twenty-nine patients completed the entire study follow-up; one patient exited from the study 3 months after HIFU and underwent trabeculectomy. At days 1 and 180, the mean IOP was significantly reduced (18.4 ± 7.2 and 20.2 ± 6.2 mmHg, respectively; all p < 0.0001). Group 3 patients (8-s ultrasound exposure time) showed a greater IOP reduction than the other two groups (-16.2 ± 8.3 for group 3 vs. -8.8 ± 6.6 for group 2 and -3.7 ± 6.5 for group 1; p = 0.02 and p < 0.001, respectively). Qualified and complete success was achieved in 23.3 and 46.7% of patients, respectively; treatment failure was recorded in 6.6%. CONCLUSIONS: Ultrasonic coagulation of the ciliary body is a safe and effective procedure for reducing IOP in refractory glaucoma. The increase in ultrasound exposure time appears to improve the response rate and the global efficacy of the procedure, with no detrimental effect on safety.

Extra-mitochondrial aerobic metabolism in retinal rod outer segments: new perspectives in retinopathies.

Vertebrate retinal rods are photoreceptors for dim-light vision. They display extreme sensitivity to light thanks to a specialized subcellular organelle, the rod outer segment. This is filled with a stack of membranous disks, expressing the proteins involved in visual transduction, a very energy demanding process. Our previous proteomic and biochemical studies have shed new light on the chemical energy processes that supply ATP to the outer segment, suggesting the presence of an extra-mitochondrial aerobic metabolism in rod outer segment, devoid of mitochondria, which would account for a quantitatively adequate ATP supply for phototransduction. Here the functional presence of an oxidative phosphorylation in the rod outer limb is examined for its relationship to many physiological and pathological data on the rod outer segment. We hypothesize that the rod outer limb is at risk of oxidative stress, in any case of impairment in the respiratory chain functioning, or of blood supply. In fact, the electron transfer chain is a major source of reactive O(2) species, known to produce severe alteration to the membrane lipids, especially those of the outer segment that are rich in polyunsaturated fatty acids. We propose that the disk membrane may become the target of reactive oxygen species that may be released by the electron transport chain under pathologic conditions. For example, during aging reactive oxygen species production increases, while cellular antioxidant capacity decreases. Also the apoptosis of the rod observed after exposure to bright or continuous illumination can be explained considering that an overfunctioning of phototransduction may damage the disk membrane to a point at which cytochrome c escapes from the intradiskal space, where it is presently supposed to be, activating a putative caspase 9 and the apoptosome. A pathogenic mechanism for many inherited and acquired retinal degenerations, representing a major problem in clinical ophthalmology, is proposed: a number of rod pathologies would be promoted by impairment of energy supply and/or oxidative stress in the rod outer segment. In conclusion we suppose that the damaging role of oxygen, be it hypoxia or hyperoxia invoked in most of the blinding diseases, acquired and even hereditary is to be seeked for inside the photoreceptor outer segment that would conceal a potential for cell death that is still to be recognized.

Biobanks and the importance of detailed phenotyping: a case study--the European Glaucoma Society GlaucoGENE project.

BACKGROUND: Dissecting complex diseases has become an attainable goal through large-scale collaborative projects under the term "biobanks." However, large sample size alone is no guarantee of a reliable genetic association study, and the genetic epidemiology of complex diseases still has many challenges to face. Among these, issues such as genotyping errors and population stratification have been previously highlighted. However, comparatively little attention has been given to accurate phenotyping. Study procedures of existing large-scale biobanks are usually restricted to very basic physical measurements and non-standardised phenotyping, based on routine medical records and health registry systems. DISCUSSION: Study procedures of existing large-scale biobanks are usually restricted. Considering that the objective of an association study is to establish genotype-phenotype correlations, it is doubtful how easily this could be achieved in the absence of accurate and reliable phenotype description. The use of non-specific or poorly defined phenotypes may partly explain the limited progress so far in glaucoma complex genetics. This report examines the European Glaucoma Society GlaucoGENE project, which is the only large multicentre glaucoma-specific biobank. Unlike previous biorepositories, this initiative focuses on detailed and standardised phenotyping and is expected to become a major resource for future studies on glaucoma.

Rarebit perimetry and frequency doubling technology in patients with ocular hypertension.

PURPOSE: To test the capability of rarebit perimetry (RP), a recent non-conventional perimetric technique, in detecting early functional damage in subjects with ocular hypertension (OHT) and to compare RP findings with those obtained by frequency-doubling technology (FDT) perimetry. METHODS: Thirty patients with OHT were matched with 30 healthy subjects. All were tested with RP and FDT. Frequency-doubling technology mean deviation (MD) and pattern standard deviation (PSD), as well as RP mean hit rate (MHR), of the two groups were analyzed. The agreement between the two techniques was tested by Kappa analysis. RESULTS: In the OHT group the mean (SD) FDT MD was 0.5 (2.1), the mean (SD) FDT PSD was 4.2 (1.6), and the mean (SD) RP MHR was 81.4 (6.7). In the control group, corresponding values were mean (SD) FDT MD 1.1 (1.4), mean (SD) FDT PSD 3.0 (0.3), mean (SD) RP MHR 96.2 (2.0). The differences between the two groups were not significant for the studied indexes. Eleven (36.6%) out of the 30 OHT eyes had abnormal RP results; 12 (40.0%) eyes had abnormal FDT results. Five (16.6%) eyes had abnormal RP and FDT findings. Only 1 eye (3.3%) in the control group had abnormal RP results and 3 eyes (10.0%) had abnormal FDT results. RP and FDT showed a moderate agreement (Kappa=0.43; 95% CI: 0.42 to 0.51). CONCLUSIONS: RP and FDT showed VF defects not shown in standard automated perimetry in the OHT group. This may be indicative of an increased risk in developing glaucoma, even if a gold standard for detecting subtle defects is not currently available. RP has the additional advantage of not requiring any expensive device to be used. The poor agreement between these techniques in identifying eyes with early damage warrants further investigations. Large longitudinal studies are needed before defining the role of RP in early glaucoma diagnosis.

Corneal thickness and visual field damage in glaucoma patients.

PURPOSE: To verify whether there was a significant correlation between central corneal thickness (CCT) and visual field damage in patients with primary open angle glaucoma (POAG). METHODS: A total of 99 eyes with POAG were consecutively recruited. Patients were classified as glaucomatous based on visual field and optic nerve head damage. All underwent applanation tonometry, Humphrey perimetry, and measurement of CCT with ultrasonic pachymetry. Based on CCT value, the sample was split at the mode in two groups (group 1<535 microm, n=49; group 2>or=535 microm, n=50). RESULTS: Entire cohort: mean CCT 554 microm+/-45.03; mean deviation (MD) -6.68 dB+/-7.32; pattern standard deviation (PSD) 5.33+/-3.75; intraocular pressure (IOP) 17.91+/-4.16 mmHg with treatment. Group 1: CCT was 504.8 microm+/-30.8; MD -9.01 dB+/-8.72; PSD 6.38+/-3.99; IOP 18.02 mmHg+/-4.66. Group 2: mean CCT 574.6 microm+/-35.03; MD -4.39 dB+/-4.70; PSD 4.25+/-3.19; IOP 17.79 mmHg+/-3.57. A significant difference was found between the two groups for both MD and PSD. Linear regression analysis showed a significant correlation between CCT and PSD (P<0.001). CONCLUSIONS: Our data show that patients with a thinner cornea had a worse MD and PSD. As a thinner CCT causes an underestimation of the true IOP, there may be a delay in the diagnosis of POAG or an inadequate estimate of the clinical course despite apparently desirable IOP applanation readings.

Direct costs of glaucoma and severity of the disease: a multinational long term study of resource utilisation in Europe.

BACKGROUND: Resource utilisation and direct costs associated with glaucoma progression in Europe are unknown. As population progressively ages, the economic impact of the disease will increase. METHODS: From a total of 1655 consecutive cases, the records of 194 patients were selected and stratified by disease severity. Record selection was based on diagnoses of primary open angle glaucoma, glaucoma suspect, ocular hypertension, or normal tension glaucoma; 5 years minimum follow up were required. Glaucoma severity was assessed using a six stage glaucoma staging system based on static threshold visual field parameters. Resource utilisation data were abstracted from the charts and unit costs were applied to estimate direct costs to the payer. Resource utilisation and estimated direct cost of treatment, per person year, were calculated. RESULTS: A statistically significant increasing linear trend (p = 0.018) in direct cost as disease severity worsened was demonstrated. The direct cost of treatment increased by an estimated 86 for each incremental step ranging from 455 euro per person year for stage 0 to 969 euro per person year for stage 4 disease. Medication costs ranged from 42% to 56% of total direct cost for all stages of disease. CONCLUSIONS: These results demonstrate for the first time in Europe that resource utilisation and direct medical costs of glaucoma management increase with worsening disease severity. Based on these findings, managing glaucoma and effectively delaying disease progression would be expected to significantly reduce the economic burden of this disease. These data are relevant to general practitioners and healthcare administrators who have a direct influence on the distribution of resources.

Long term effect on IOP of a stainless steel glaucoma drainage implant (Ex-PRESS) in combined surgery with phacoemulsification.

AIM: To evaluate the efficacy and safety of a stainless steel miniature glaucoma drainage device (Ex-PRESS R50) for the surgical treatment of primary open angle glaucoma (POAG) and cataract when combined with phacoemulsification. METHODS: Clinical, prospective, multicentre, single treatment arm, non-randomised, non-masked study. The Ex-PRESS device was implanted at the limbus under a conjunctival flap. Phacoemulsification cataract extraction and in the bag IOL implantation were performed through clear cornea temporally. PRIMARY OUTCOME: IOP change; secondary outcomes: side effects and VA changes. RESULTS: 26 eyes of 25 patients were implanted with the device. The mean (SD) follow up was 23.9 (10.4) months and the mean age was 75.1 (7.1) years. 17/26 eyes have more than 3 years of follow up. One case was discontinued because of device removal, one because of death, and three were lost to follow up. EFFICACY: preoperative IOP was 21 (4) mm Hg; at 1, 2, and 3 years IOP was 15.3 (3.1) mm Hg (35% reduction), 16.6 (2.7) mm Hg (29% reduction), and 16 (2.6) mm Hg (22% reduction) respectively. Kaplan-Meyer determined overall success rate (IOP < or = 21 mm Hg at the last visit with or without medications) as 76.9%. The number of antiglaucoma medications was reduced by 95% at year 1. Only six patients (23%) were taking IOP lowering treatment at their last visit, five with one medication and one with two medications. Side effects: early postoperative complications were clinically mild and included six cases of hypotony (IOP <5 mm Hg), three cases of hyphaema (<2 mm) with no clinically significant further effects. Long term complications were two cases (7.7%) of device rotation (one treated by reposition) and three cases (11.5%) of conjunctival erosion at 2 and 3 years. CONCLUSIONS: The Ex-PRESS implant, combined with phacoemulsification cataract extraction, is clinically safe and effective, maintaining in the long term a large reduction in IOP and in the number of antiglaucoma medications.

Comparison between relative dispersion analysis of high-pass resolution perimetry and standard threshold perimetry.

PURPOSE: To evaluate the correlation of the dispersion index (DI) of relative dispersion analysis (RDA), a new high-pass resolution perimetry (HRP) index, with other HRP indices and those of the Humphrey standard threshold perimeter (STP) parameters. METHODS: Sixty-eight eyes were randomly recruited. Thirty-one eyes were classified as glaucomatous (high intraocular pressure, abnormal visual field and/or optic disc) and 37 as ocular hypertensives (high intraocular pressure, normal visual field, normal optic disc). All the subjects were examined with Humphrey Perimeter, program 30-2, and HRP. The HRP data were also analysed with the RDA program. Statistical analysis was performed with Student's t-test, Pearson's r correlation coefficient, Mann-Whitney nonparametric test and Spearman correlation coefficient when appropriate. RESULTS: Within the entire sample significant correlations were found between the RDA index (DI) and all the HRP indices (p < 0.001) and corrected pattern standard deviation (p < 0.01), pattern standard deviation (PSD) (p < 0.01), mean deviation (p < 0.05) and short-term fluctuation (p < 0.05) of STP. A stronger correlation was found in glaucomatous patients. In subjects with ocular hypertension DI was only weakly correlated with PSD, local deviation and form index. No difference in DI was found between glaucoma and ocular hypertension. CONCLUSION: The DI of HRP has the theoretical capacity to detect localised inhomogeneity of retinal sensitivity, but at present our data do not support this hypothesis. Before any clinical applications of this index further studies are needed.

Learning effect, short-term fluctuation, and long-term fluctuation in frequency doubling technique.

PURPOSE: To evaluate short-term and long-term fluctuations and learning effects in healthy subjects tested with the frequency doubling technique, which is based on a low spatial frequency and a high temporal frequency stimulus. METHODS: Twenty-three healthy adult subjects were consecutively recruited from volunteers, and 20 subjects finished the study. All the visual fields were assessed by the frequency doubling technique, program C-20, full threshold. The frequency doubling technique presents stimuli on a black-and-white video monitor with specialized control circuitry interfaced to a microprocessor. During program C-20, full threshold, 17 points are tested, one round point centrally and 16 square ones in the periphery up to 20 degrees of eccentricity. Each stimulus consists of a 0.25-cycle/degree sinusoidal grating undergoing a 25-Hz counterphase flicker. One eye of each patient was chosen at random. Each subject was tested once in the first session, three times in the second session, and once in the third and fourth sessions. Both short-term and long-term fluctuation were studied either as the average fluctuation value of all the points tested or as a point-to-point fluctuation. To study the learning effect, the results of the first session were compared with those of the second, the third, and the fourth sessions. RESULTS: The average mean sensitivity of the three examinations of the second session was 30.4 +/- 1.24 dB, and the average short-term fluctuation of all the subjects was 2.16 +/- 0.5 dB. The short-term fluctuation of each point tested ranged from 1.4 to 3.4 dB. The average mean sensitivity for all the sessions was 32.4 +/- 1.14 dB, with an average long-term fluctuation of 3.23 +/- 0.5 dB, and the long-term fluctuation of each tested point ranged from 2.5 to 4.4 dB. A mild learning effect was found between the first section and the others. CONCLUSION: Short-term and long-term fluctuations were similar to those known to occur with the conventional threshold perimetry when they were compared with the literature data. A learning effect was also observed and should be taken into account for the clinical use of this test.

Reliability of applanation tonometry readings obtained with a disposable latex cap.

BACKGROUND: To verify the accuracy of applanation tonometry through disposable latex caps used to prevent transmission of infectious diseases. METHODS: Tonometry was performed in 80 patients. Each patient underwent two intraocular pressure (IOP) measurements with and without the latex. In group A patients tonometry was performed first without the cap; in group B tonometry was performed first with the cap. Each group was also divided into patients with IOP, >/=20 mm Hg (A1; B1) and patients with IOP <20 mm Hg (A2; B2). RESULTS: The mean difference of tonometry readings was equal to -0.36 +/- 1. 62 mm Hg in group A, -0.03 +/- 1.77 mm Hg in group A1, -0.61 +/- 1. 45 mm Hg in group A2, 0.23 +/- 1.44 in group B, 0.64 +/- 1.41 mm Hg in group B1, 0.05 +/- 1.42 in group B2. A statistically significant correlation was found in group A, in group A2, B, B1 and B2; a less significant correlation was found in group A1. CONCLUSIONS: The use of the latex caps does not alter the reliability of tonometry readings as long as the cap is applied tightly. Measurement variation in our study is comparable to published data on applanation tonometry.

Correlation between high-pass resolution perimetry and standard threshold perimetry in subjects with glaucoma and ocular hypertension.

PURPOSE: To evaluate the correlation between High-Pass Resolution Perimetry (HRP) and standard threshold perimetry in patients with glaucoma or ocular hypertension. METHODS: 31 glaucomatous patients and 37 ocular hypertension subjects with previous perimetric examination experience were consecutively recruited and only one eye for each patient was selected at random. Glaucomatous patients were classified as having primary open angle glaucoma when they had an abnormal visual field and/or an abnormal optic nerve head (ONH)/retinal nerve fiber layer (RNFL) typical of glaucoma, open angle at gonioscopy and no clinically apparent secondary cause for their glaucoma. Ocular hypertension subjects were defined as having intraocular pressure >21 mm Hg on no treatment, normal visual field, normal ONH and RNFL, elevated intraocular pressure without any treatment. All the subjects were examined with Humphrey Field Analyzer (HFA) 640, 'program central 30-2' (Humphrey Systems, San Leandro, CA, USA) and with High-Pass Resolution Perimeter (HRP), Ophthimus version 2.4,'ring program' (Nikon-HighTech Vision, Goteborg, Sweden). Visual field indices were obtained with both systems: for HFA mean deviation (MD), corrected pattern standard deviation (CPSD) and short term fluctuation (SF), while for HRP global deviation (GD), local deviation (LD), form index (FI) and neural capacity (NC). The data were analyzed by descriptive analysis, Student's t test with Bonferroni's correction or Mann-Whitney non-parametric test and Pearson or Spearman's correlation coefficient. RESULTS: A significant correlation was found between MD and GD (r = -0.81), CPSD and LD (r = 0.87), PSD and LD (r = 0.72). NC was significantly correlated with MD (r = 0.76), GD (r = -0.94). FI was significantly correlated with PSD (r = -0.58), CPSD (r = -0.72), LD (r = -0.56). When the same data were analyzed for the glaucomatous group only, similar results were found; in the ocular hypertensive group no significant correlation was found except between NC and MD (r = 0.52). CONCLUSION: HRP indices vary comparably with HFA indices. Parameters as NC and FI were significantly correlated with standard visual field indices of both HFA and HRP. Although the clinical applications for FI are not clear yet, NC could detect both early glaucomatous damage and age related changes.