Comparing Half-Dose Photodynamic Therapy with Subthreshold Micropulse Laser for the Treatment of Central Serous Chorioretinopathy.

PURPOSE: To compare the anatomic and functional outcomes of half-dose photodynamic therapy (PDT) and yellow 577-nm subthreshold micropulse laser (SMLT) in treating patients with chronic central serous chorioretinopathy (CSCR). DESIGN: Prospective, double-masked, randomized, controlled clinical trial. PARTICIPANTS: Patients with chronic CSCR confirmed by clinical features and multimodal imaging. METHODS: Eligible patients were randomized (1:1) to receive half-dose PDT or SMLT. The same treatment was repeated if persistent subretinal fluid (SRF) was observed. Treatment responses were evaluated 1 month after treatment and every 3 months until the end point at 12 months. MAIN OUTCOME MEASURES: The primary outcome measure was the complete resolution of SRF on OCT scan at month 12. Secondary outcomes included the changes in best-corrected visual acuity (BCVA), central macular thickness (CMT) as measured by OCT, retinal sensitivity as measured by microperimetry, and vision-related quality of life using the National Eye Institute 25-Item Visual Function Questionnaire. RESULTS: Between April 2017 and October 2020, 68 patients were recruited. At 1 month after treatment, SRF resolved in 8 (24.2%) of 33 patients receiving SMLT and in 20 (58.8%) of 34 patients receiving half-dose PDT. This increased to 23 (82.1%) of 28 patients in the SMLT group and 30 (90.9%) of 33 patients in the half-dose PDT group at 12 months of follow-up. Kaplan-Meier survival curves showed significantly faster resolution of SRF in the half-dose PDT group than the SMLT group (P = 0.016). Both groups showed significant improvement in BCVA (-0.12 ± 0.21, P = 0.005 for SMLT; -0.13 ± 0.12, P < 0.001 for half-dose PDT), CMT (-154.2 ± 105.6, P < 0.001 for SMLT; -140.8 ± 94.0, P < 0.001 for half-dose PDT), and retinal sensitivity (5.70 ± 5.02, P < 0.001 for SMLT; 6.05 ± 3.83, P < 0.001 for half-dose PDT) at 12 months compared with baseline. There was no significant difference between the 2 treatment groups at each time point in all investigations except BCVA at 3 months (P = 0.03). CONCLUSIONS: When comparing half-dose PDT to subthreshold SMLT, this study has shown both treatments to be viable options, with half-dose PDT achieving faster anatomic success and functional improvement. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Comparing the Rise in Glucose Concentration in Blood, Aqueous and Interstitial Fluid During a Glucose Tolerance Test.

Purpose: The purpose of the study was to determine if aqueous glucose levels rise in a comparable time frame to interstitial fluid and could therefore be suitable for a continuous glucose monitoring (CGM) site. Methods: An intravenous glucose tolerance test was performed on five New Zealand white rabbits. Aqueous humor from the posterior and anterior chamber of the eye and venous blood were sampled for glucose concentration measurement. Glucose concentrations in the interstitial fluids were monitored using a CGM system. A compartment model was created to map the glucose response curves in each compartment. The delay in rising glucose concentrations between blood and interstitial fluid and aqueous humor in the posterior chamber and anterior chamber of the eye were analyzed. Results: The results showed a statistically similar time lag and rate of change in glucose concentrations between blood and interstitial fluids or aqueous humor in either the posterior or anterior chamber. Conclusions: The results of this study add further support to the aqueous humor being used as an alternative CGM site. Translational Relevance: The study provides the basis for developing an intraocular continuous glucose sensor that can overcome limitations of current CGM systems.

Evaluation of Electrical Performance and Properties of Electroretinography Electrodes.

Purpose: The aim of this study was to evaluate and compare the electrical performance and properties of commercially available electroretinography (ERG) electrodes. Methods: A passive ionic model was used to measure impedance, noise, and potential drift in 10 types of ocular surface and skin ERG electrodes. Results: The impedance for silver-based ocular electrodes are generally lower (range, 65.35-343.3 Ω) with smaller phase angles (range, -6.41° to -33.91°) than gold-based electrodes (impedance ranged from 285.95 Ω to 2.913 kΩ, and phase angle ranged from -59.65° to -70.01°). Silver-based ocular electrodes have less noise (median line noise of 6.48 x 104nV2/Hz) than gold-based electrodes (median line noise of 2.26 x 105nV2/Hz). Although silver-based electrodes usually achieve a drift rate less than 5 µV/s within 15 minutes, gold-base ocular electrode cannot achieve a stable potential. The exception is the RETeval strip type of silver electrode, which had an unusual drift at 20 minutes. The noise spectral density showed no change over time indicating that noise was not dependent on the stabilization of the electrode. Conclusions: From the range of electrodes tested, lower impedance, lower capacitance, and lower noise was observed in silver-based electrodes. Stabilization of an electrode is effective against drift of the electrode potential difference but not the noise. Translational Relevance: Application of electrodes with optimized materials improve the quality of clinical electrophysiology signals and efficiency of the recording.

Intracameral injection of a chemically cross-linked hydrogel to study chronic neurodegeneration in glaucoma.

Investigation of neurodegeneration in glaucoma, a leading cause of irreversible blindness worldwide, has been obfuscated by the lack of an efficient model that provides chronic, mild to moderate elevation of intraocular pressure (IOP) with preservation of optical media clarity for long term, in vivo interrogation of the structural and functional integrity of the retinal ganglion cells (RGCs). Here, we designed and formulated an injectable hydrogel based on in situ cross-linking of hyaluronic acid functionalized with vinyl sulfone (HA-VS) and thiol groups (HA-SH). Intracameral injection of HA-VS and HA-SH in C57BL/6J mice exhibited mild to moderate elevation of IOP with daily mean IOP ranged between 14 ±â€¯3 and 24 ±â€¯3 mmHg, which led to progressive, regional loss of RGCs evaluated with in vivo, time-lapse confocal scanning laser ophthalmoscopy; a reduction in fractional anisotropy in the optic nerve and the optic tract projected from the eye with increased IOP in diffusion tensor magnetic resonance imaging; a decrease in positive scotopic threshold response in electroretinography; and a decline in visual acuity measured with an optokinetic virtual reality system. The proportion of RGC loss was positively associated with the age of the animals, and the levels and the duration of IOP elevation. The new glaucoma model recapitulates key characteristics of human glaucoma which is pertinent to the development and pre-clinical testing of neuroprotective and neuroregenerative therapies. STATEMENT OF SIGNIFICANCE: A new model to study chronic neurodegeneration in glaucoma has been developed via intracameral injection of a specifically designed hyaluronic acid functionalized with vinyl sulfone and thiol groups for cross-linking. Intracameral injection of the chemically cross-linked hydrogel generates mild to moderate IOP elevation, resulting in progressive degeneration of the retinal ganglion cells, optic nerve, and optic tract, and a decline in visual function. The model recapitulates the key features of neurodegeneration in human glaucoma, which will facilitate and expedite the development of neuroprotective and neuroregenerative therapies.

The Evolving Story of Pterygium.

Pterygium is a fibrovascular subepithelial growth of degenerative tissue over the limbus. It is a common condition worldwide that is especially prevalent in tropical countries within the "pterygium belt." Its exact etiology remains to be elucidated; however, it is strongly associated with exposure to ultraviolet light. The high expression levels of tumor protein p53 (TP53) observed in laboratory studies of pterygium seem to contradict the fast-growing nature of its clinical behavior, and TP53 mutations have been suggested. We demonstrated that mouse double minute 2 (MDM2), a TP53-binding protein, contributes to the inhibition of TP53 activity in human pterygium. Thus, disruption of the MDM2-TP53 interaction should attenuate human pterygium cell growth. For primary pterygium, treatment is relatively straightforward and involves surgical excision. To minimize the risk of recurrence, many adjunctive therapies are adopted, including antimetabolites, such as mitomycin C and 5-fluorouracil, amniotic membrane, different variations on conjunctival and/or limbal conjunctival grafts, and other medications such as anti-vascular endothelial growth factor. In the future, MDM2 antagonists may help further lower the recurrence rates after the treatment of pterygium.

p53 inhibition by MDM2 in human pterygium.

AIMS: To confirm that mouse double minute 2 (MDM2) could inhibit p53 activity in human pterygium. And to show the disruption of MDM2-p53 interaction could reactive the functions of p53 in pterygium. METHOD: Pterygium and corresponding conjunctiva tissues were collected for establishment of primary cell lines. Expression patterns of MDM2 and p53 were detected by immunofluorescence. Protein localization of p53 and MDM2, and transcriptional activity of p53 in both untreated and MDM2 antagonist (Nutlin) treated pterygium cells were quantified. RESULTS: In pterygium, p53 was highly expressed in cytoplasm and slightly expressed in the nuclei. MDM2 was localized in the nuclei. A p53 transcriptional regulated target gene, p21, was not expressed in pterygium tissues, suggesting the p53 transcriptional activity was not active in pterygium. After treatment with Nutlin, increased nuclear localization of p53 (4.05%-80.56%) was observed in pterygium cells along with increasing Nutlin dosages (from 0 to 50 µM, p < 0.001). The expression of p21 was increased after Nutlin treatments in pterygium cells (2.49 folds in 20 µM Nutlin treated cells compared to control treated cells, p = 0.012). CONCLUSION: We discovered a novel mechanism in pterygium whereby MDM2 suppresses p53 transcriptional activity despite abundant p53 in pterygium. Disruption of MDM2-p53 interaction by Nutlin could be a potential treatment for pterygium.

Cellular Proliferation and Migration of Human Pterygium Cells: Mitomycin Versus Small-Molecule Inhibitors.

PURPOSE: Nutlin is a drug that has been reported to activate p53 in various cell lines. We aim to study the effects of Nutlin in pterygium and compare the effects of Nutlin and mitomycin C (MMC) in pterygium cell lines. METHODS: Pterygium samples (n = 3) were collected during surgical excision. Normal conjunctival tissues (n = 3) were collected from another quadrant of the same eye. Cell lines were established, and cells from passages 2 to 5 were used. Pterygium and conjunctival cells were treated with different doses of Nutlin and MMC. Cell proliferation and cell migration were measured. RESULTS: Cell proliferation was reduced by 39-fold after treatment with 50 µM Nutlin. Cell migration was inhibited with increasing dosages of Nutlin (95% and 28% after treating with 2 and 50 µM Nutlin, respectively). Compared with MMC, Nutlin induced more pterygium cell death and less conjunctival cell death at low doses. At 50% lethal dose for pterygium cells, 95% of conjunctival cells survived after Nutlin treatment, whereas only 63% of conjunctival cells survived after MMC treatment. p21 expression was not detectable in MMC-treated pterygium cells but was detectable after Nutlin treatment. CONCLUSIONS: In our study, MMC induced cell death in pterygium and conjunctival cell lines, whereas Nutlin had a targeted impact on pterygium cells. Our results implied that MMC inhibited both pterygium cell proliferation and migration through an apoptosis-independent pathway.

Conventional Versus Inverted Side-cut Flaps for Femtosecond Laser-Assisted LASIK: Laboratory and Clinical Evaluation.

PURPOSE: To study the differences in early corneal cellular events and biomechanical properties after femtosecond laser-assisted LASIK performed using conventional or inverted side-cut angles. METHODS: In the laboratory study, left eyes of 24 rabbits underwent LASIK flap creation with a 70° or 115° side-cut. The contralateral eyes served as controls. The corneas were harvested 24 hours postoperatively. In the clinical study, 2 eyes of each patient (n = 29) were randomized to corneal flap creation with 70° or 115° side-cut angles during LASIK. The Ocular Response Analyzer (ORA; Reichert Ophthalmic Instruments, Depew, NY) was used to assess biomechanical properties of the cornea. RESULTS: In rabbit eyes, epithelial ingrowth was observed more frequently in flaps with 70° side cuts compared to flaps with 115° side-cuts. Corneas with 70° side-cuts showed significantly increased apoptotic cells compared to 115° side-cuts in the central (P = .001) and peripheral (P = .004) regions. Fifty-eight eyes of 29 patients were included in the clinical study. An overall reduction in Goldmann-correlated intraocular pressure, corneal-compensated intraocular pressure, corneal resistance factor, corneal hysteresis measurements, p1 area, p2 area, and p1 area 1 and p2 area 1 was noted 37 ± 2 months after surgery (P < .001). No significant difference was observed in the change of any of these parameters between both groups (P ≥ .146). CONCLUSIONS: Significant differences in wound healing were observed in rabbit corneas that underwent LASIK with conventional or inverted side-cuts. Variation in flap side-cut angles did not alter the long-term biomechanical properties measured with the ORA in patients after LASIK. [J Refract Surg. 2017;33(2):96-103.].

Green tea catechins are potent anti-oxidants that ameliorate sodium iodate-induced retinal degeneration in rats.

Green tea extracts exhibit anti-oxidative and anti-inflammatory actions in different disease conditions. We hypothesized that green tea extract and its catechin constituents ameliorate sodium iodate-induced retinal degeneration in rats by counteracting oxidative stress. In this study, adult Sprague-Dawley rats were intravenously injected with a single dose of sodium iodate. Green tea extract (GTE; Theaphenon-E) or combinations of its catechin constituents, including (-)-epigallocatechin gallate (EGCG), were administered intra-gastrically before injection. Live imaging analysis using confocal scanning laser ophthalmoscopy and spectral-domain optical coherence tomography showed a progressive increase of degenerating profile across the retinal surface and decrease in thickness of outer nuclear layer (ONL) at Day-14 of post-injection. These lesions were significantly ameliorated by Theaphenon-E and catechin combinations with EGCG. Catechins with exclusion of EGCG did not show obvious protective effect. Histological analyses confirmed that Theaphenon-E and catechins containing EGCG protect the retina by reducing ONL disruption. Retinal protective effects were associated with reduced expression of superoxide dismutase, glutathione peroxidase and caspase-3, and suppression of 8-iso-Prostaglandin F2α generation in the retina. In summary, GTE and its catechin constituents are potent anti-oxidants that offer neuroprotection to the outer retinal degeneration after sodium iodate insult, among which EGCG is the most active constituent.

Randomized, contralateral eye study to evaluate the effect of standard and inverted side-cut angle on corneal biomechanical properties during femtosecond laser-assisted in situ keratomileusis.

PURPOSE: To evaluate the effect of side-cut angle profile on corneal biomechanical properties after femtosecond laser in situ keratomileusis (FS-LASIK). METHODS: Ninety-six myopic eyes of 48 patients underwent FS-LASIK. One eye of each patient was randomized to flap creation with a side-cut angle of 115°. The fellow eye flap side-cut angle was adjusted to 70°. Mean absolute error of flap diameter and mean change in Goldmann-correlated intra-ocular pressure (IOPg), corneal-compensated IOP (IOPcc), corneal hysteresis (CH), corneal resistance factor (CRF), p1 area, p2 area, p1 area 1 and p2 area 1 were compared between both groups. RESULTS: Overall, the mean IOPg and CRF showed significant reduction at the end of 1 and 3 months, as well as between 1 and 3 months postoperatively (p ≤ 0.03). The mean IOPcc and CH showed significant reduction (p < 0.001) at the end of 3 months postoperatively. The parameters p1 area, p2 area, p1 area 1 and p2 area 1 changed significantly at the end of 1 and 3 months postoperatively (p < 0.001). There was no significant difference between both groups with regards to the mean change of IOPg, IOPcc, CH, CRF, p1 area, and p1 area 1. In 115° group, the mean absolute error in flap diameter was greater compared with 70° group (p = 0.014). CONCLUSIONS: The stability of IOP and corneal biomechanical properties were not enhanced in FS-LASIK flaps with an inverted side-cut angle. The size of corneal flap created with 70° side-cut angle was more accurate compared with 115° side-cut angle.

Assessing sodium iodate-induced outer retinal changes in rats using confocal scanning laser ophthalmoscopy and optical coherence tomography.

PURPOSE: Sodium iodate induces RPE atrophy and photoreceptor degeneration, as seen in the pathogenesis of many retinal diseases. We investigated a new approach of analyzing retinal images using confocal scanning laser ophthalmoscopy (cSLO) that allows longitudinal assessment of sodium iodate-induced lesions in the retina of living rats. METHODS: A single dose of sodium iodate (25-75 mg/kg) was given intravenously to adult Sprague-Dawley rats. Control animals were given normal saline or sodium iodide. The retina was examined by cSLO and optical coherence tomography (OCT) in living rats, which were then killed for histologic assessments. RESULTS: Confocal scanning laser ophthalmoscopy revealed the appearance of dark patchy blots in planar images of the retina 7 days after intravenous injection of sodium iodate (25-75 mg/kg). This finding coincided with the observations of degenerative changes in the outer retinal layers in OCT images and in histology of the retina. Further analyses showed a concomitant localization of degenerative profiles in histologic preparations of this retina, suggesting that the blots corresponded to the deteriorating photopigments and outer nuclear layer (ONL). In histologic sections, these degenerative profiles appeared as irregular folds or rosettes in the ONL. Quantitative analyses showed that the changes in blot number were dose dependent, which again coincided with results showing a dose-dependent lesion in the photopigment layer and ONL in histologic sections of the retina. CONCLUSIONS: Sodium iodate-induced degenerative changes can be assessed quantitatively and reliably by in vivo retinal imaging using cSLO in adult rats, allowing efficient evaluation of lesions in a large area of retina in longitudinal studies.

Improvement in multifocal electroretinography after half-dose verteporfin photodynamic therapy for central serous chorioretinopathy: a randomized placebo-controlled trial.

PURPOSE: To evaluate retinal functional changes by multifocal electroretinography (mfERG) after photodynamic therapy with half-dose verteporfin in patients with acute central serous chorioretinopathy. METHODS: Thirty-four patients with acute central serous chorioretinopathy were randomly assigned to receive photodynamic therapy with half-dose verteporfin (n = 24) or placebo (n = 10). Multifocal electroretinography was performed at baseline and at 12 months, and serial changes in response amplitudes were expressed as amplitude ratios. The mfERG amplitude ratios, best-corrected visual acuity, and optical coherence tomography central foveal thickness were compared between the verteporfin and placebo groups. Correlation analysis between the mfERG response amplitude ratios and the best-corrected visual acuity changes and reduction in optical coherence tomography central foveal thickness were also performed. RESULTS: At 12 months, the mean visual improvement was 1.8 line and 0.1 line for the verteporfin and placebo groups, respectively (P = 0.003). Eyes in the verteporfin group had significantly lower central foveal thickness (P = 0.028) and higher P1 mfERG response ratios for Rings 1 and 2 at 12 months compared with the eyes in the placebo group (P = 0.030 and P = 0.018, respectively). Significant correlations between mfERG N1 and P1 amplitude ratios at the central rings were observed with both changes in best-corrected visual acuity and reductions in optical coherence tomography central foveal thickness (P < 0.05). CONCLUSIONS: Multifocal electroretinography demonstrated higher retinal function at the central macula objectively in central serous chorioretinopathy patients treated with half-dose verteporfin photodynamic therapy. Changes in best-corrected visual acuity and optical coherence tomography central foveal thickness findings also correlated with mfERG responses of the central macula, confirming the usefulness of mfERG as an objective investigation to evaluate the functional changes in central serous chorioretinopathy.

Correlation between functional and anatomical assessments by multifocal electroretinography and optical coherence tomography in central serous chorioretinopathy.

To evaluate the correlation between functional and anatomical assessments with multifocal electroretinography (mfERG) and optical coherence tomography (OCT) in patients with acute central serous chorioretinopathy (CSC). Thirty-four eyes of 34 patients with acute CSC underwent mfERG and OCT examinations. First-order mfERG N1 and P1 response amplitudes and latencies were analyzed.OCT parameters measured included central subretinal fluid (SRF) thickness, central retinal thickness, total central foveal thickness, vertical, and horizontal diameters of SRF, and macular volume. Correlation analyses were performed between best-corrected visual acuity (BCVA), mfERG parameters, and OCT measurements. Correlation analysis showed that logMAR BCVA was significantly correlated with mfERG N1 amplitudes of rings 1 and 2 (P = 0.006), N1 latency of ring 4 (P = 0.012), and P1 latency of ring 1 (P = 0.036). No significant correlation was observed between logMAR BCVA and any of the OCT measurements. For the correlation between mfERG parameters and OCT measurements, mfERG N1 and P1 latencies of the paracentral rings were significantly correlated with the central SRF thickness (P < or = 0.024), diameters of the SRF (P < or = 0.018), and macular volume (P < or = 0.030). MfERG responses but not OCT measurements correlated with logMAR BCVA in patients with acute CSC. The amount of SRF nonetheless correlated with the mfERG N1 and P1 latencies of the paracentral rings, suggesting that impairment in the conduction of electrical responses in the paracentral macula is proportional to the severity of serous macular detachment in CSC. MfERG and OCT can complement each other in the functional and anatomical assessments in CSC.

Changes in first- and second-order multifocal electroretinography in idiopathic macular hole and their correlations with macular hole diameter and visual acuity.

PURPOSE: To evaluate the first- and second-order multifocal electroretinography (mfERG) responses in patients with idiopathic macular hole, and their correlations with macular hole diameter measured by optical coherence tomography (OCT) and visual acuity. METHODS: Twenty-four eyes of 24 patients with idiopathic macular hole underwent mfERG and OCT examinations. The response amplitudes and implicit times of the first- and second-order mfERG were analyzed and compared with 20 age-similar normal control subjects. Correlation analyses between visual acuity, apical and basal diameters of the macular hole, and the first- and second-order mfERG amplitudes and implicit times were performed. RESULTS: The first-order mfERG N1 and P1 amplitudes in the central two concentric rings were reduced in macular hole eyes compared with controls (p < 0.006). For the second-order mfERG, only the N1 mfERG amplitude was significantly reduced at ring 6 in macular hole eyes compared with controls (p = 0.030). Correlation analysis showed that apical diameter of macular hole was significantly correlated with the first-order N1 amplitude of rings 2 to 5 (p < 0.024), the first-order P1 amplitude of rings 2 to 6 (p < 0.05), as well as the second-order P1 mfERG amplitudes of rings 3 to 6 and N1 amplitudes of rings 3 to 5 (p < 0.05). LogMAR visual acuity showed significant correlation with apical diameter of the macular hole (p = 0.002), and also with the first-order P1 amplitude of ring 2 (p = 0.024). CONCLUSION: In eyes with idiopathic macular hole, reductions in first-order mfERG responses are limited to the central macula, while the second-order mfERG response abnormalities involved more of the peripheral macular region. OCT measurement of apical and not the basal diameter of macular hole correlated with the severity of retinal dysfunction assessed by both mfERG and visual acuity.