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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Extracapsular cataract extraction using a temporal limbal approach after filtering operations.

We reviewed the charts of 29 patients who underwent extracapsular cataract extraction after filtering surgery. Seven of these patients also had simultaneous implantation of a posterior chamber intraocular lens. All eyes were operated on using a temporal limbal approach. The median postoperative follow-up was 13 months. There was no statistically significant difference between the preoperative and postoperative intraocular pressures, but there tended to be an increase in the number of antiglaucoma medications administered postoperatively. None of these patients, however, required further surgery for intraocular pressure control.

Neodymium-YAG laser iridotomy in the treatment and prevention of angle closure glaucoma. A review of 373 eyes.

The records of 271 consecutive patients (373 eyes) who underwent neodymium-YAG laser iridotomy at our institution over a period of 12 months were reviewed. The majority of eyes (60.5%) were treated for chronic primary angle closure glaucoma, 23.3% had prophylactic iridotomy for occludable angles, 7.8% were treated for acute angle closure glaucoma, 3.2% required iridotomy for the relief of iris bombé secondary to anterior uveitis, and the rest (5.2%) were treated for miscellaneous causes of secondary angle closure. Laser iridotomy, with or without medical treatment, obviated further surgical treatment in most categories of eyes. Visual acuity remained unchanged or improved in the great majority (92%) of cases over the period of follow-up (range, two to 12 months; median, four months). Visual deterioration in 8% of eyes was attributed to the usual causes, such as normal cataract progression, but none was believed to be related to the laser treatment. This article discusses the advantages of the neodymium-YAG laser (over argon) for performing iridotomies.

Neodymium-YAG laser goniotomy vs surgical goniotomy. A preliminary study in paired eyes.

Goniotomy and trabeculotomy are two widely accepted modalities of treatment for primary congenital/infantile glaucoma. Both procedures may be associated with complications. We treated 10 patients with bilateral, symmetrical congenital/infantile glaucoma and clear corneas. One eye of each patient underwent surgical goniotomy under general anesthesia, and the other was treated by neodymium-YAG laser goniotomy under oral chloral hydrate sedation (average energy, 76.6 mJ). Mean pretreatment intraocular pressure in the surgical goniotomy group was 28.4 mm Hg and in the laser goniotomy group it was 29.5 mm Hg, decreasing to 23.6 and 23.1 mm Hg, respectively, following treatment. There was a strong positive correlation (r = .81) between the percent of intraocular pressure change after laser treatment (mean, -14.4%) and that after surgery (mean, -14.3%). Our preliminary results indicate that neodymium-YAG laser goniotomy is an effective, noninvasive alternative to surgical goniotomy.

Formation of peripheral anterior synechiae following argon laser trabeculoplasty. A prospective study to determine relationship to position of laser burns.

One hundred eighteen eyes with primary open-angle glaucoma underwent argon laser trabeculoplasty . Laser burns were placed in the anterior trabecular meshwork (ATM) in 58 eyes and directly over Schlemm's canal in the posterior trabecular meshwork (PTM) in 60 eyes. Twenty-nine eyes received 100 burns and 89 eyes received 50 burns distributed equally over 360 degrees. Peripheral anterior synechiae (PAS) developed in seven (12%) of the eyes having anterior trabeculoplasty and in 26 (43%) of those having posterior trabeculoplasty . There was no correlation between the development of PAS and sex, width of the anterior chamber angle, or the number of laser burns. Eyes having anterior trabeculoplasty had a final decrease in intraocular pressure equal to those having posterior trabeculoplasties . Our results strongly suggest that trabeculoplasty is a safer but no less effective procedure when the laser burns are placed on the ATM rather than the PTM.

Aqueous misdirection and flat chamber after posterior chamber implants with and without trabeculectomy.

Three patients developed flat anterior chamber and were ultimately diagnosed as having aqueous misdirection after trabeculectomy with extracapsular cataract extraction and posterior chamber lens implantation (glaucoma triple procedure). A fourth patient developed aqueous misdirection after posterior chamber lens implantation only (without trabeculectomy). This latter was cured by repeated pars plana vitrectomy, not requiring removal of the pseudophakos. In only one of the three eyes with the triple procedure did the lens have to be removed and anterior vitrectomy performed, whereas the remaining two were cured by neodymium-YAG laser disruption of the anterior hyaloid. In these two cases, the posterior capsule remained intact. Neodymium-YAG laser vitreolysis should be the first step in the management of these cases because of its safety compared with open surgery.

The glaucomas in aphakia and pseudophakia.

Intraocular pressure may become temporarily or permanently elevated at various intervals following cataract surgery. There are several mechanisms by which glaucoma develops as a complication of the cataract extraction itself. The presence of a pseudophakos may or may not contribute to the pathogenesis. Important diagnostic clues include the anterior chamber depth, the presence or absence of an iridectomy, gonioscopic findings, and the appearance of the optic nerve head. Life-long medical treatment is frequently justified, as alternative laser or surgical modalities may not be successful. The exact causes for high failure of filtration surgery in aphakic eyes is not clearly understood; scarring of the conjunctiva, the vitreous, and altered characteristics of the aqueous humor have all been incriminated. Current research to improve surgical success includes the development of effective artificial drainage implants or the use of pharmacologic modulators of wound healing, which promote filtration by preventing scar formation.

Neodymium-YAG laser posterior capsulotomy for the treatment of aphakic and pseudophakic pupillary block.

We examined five patients who developed pupillary block after extracapsular cataract extraction. One of the patients also had a posterior chamber intraocular lens implanted at the time of cataract operation. In all five patients, pupillary block was promptly relieved by Nd:YAG laser posterior capsulotomy.

Limbal- vs fornix-based conjunctival trabeculectomy flaps.

We studied 20 patients with uncontrolled symmetric glaucoma who had undergone bilateral trabeculectomy after having received the same medical or laser treatment to both eyes. In each patient, the techniques and suture material used in the two eyes were identical, and the surgeon was the same. The only variable was the type of conjunctival flap used: one eye received a limbal-based flap and the other a fornix-based flap. These patients were followed up from three to 13 months (median, 8.5 months). There was no difference between the two groups in postoperative anterior chamber depth, intraocular pressure control, occurrence of hyphema, size and shape of the bleb, or the rate of complications. The fornix- and limbal-based conjunctival flaps in trabeculectomy were found to yield comparable results in terms of safety and short-term efficacy of pressure control.

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.

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.