A Model of Progression to Help Identify Macular Damage Due to Glaucoma.

The central macula contains a thick donut shaped region of the ganglion cell layer (GCL) that surrounds the fovea. This region, which is about 12 degrees (3.5 mm) in diameter, is essential for everyday functions such as driving, reading, and face recognition. Here, we describe a model of progression of glaucomatous damage to this GCL donut. This model is based upon assumptions supported by the literature, and it predicts the patterns of glaucomatous damage to the GCL donut, as seen with optical coherence tomography (OCT). After describing the assumptions and predictions of this model, we test the model against data from our laboratory, as well as from the literature. Finally, three uses of the model are illustrated. One, it provides an aid to help clinicians focus on the essential central macula and to alert them to look for other, non-glaucomatous causes, when the GCL damage does not fit the pattern predicted by the model. Second, the patterns of progression predicted by the model suggest alternative end points for clinical trials. Finally, the model provides a heuristic for future research concerning the anatomic basis of glaucomatous damage.

Novel utilisation of ultrawide-field fundus photography for detecting retinal nerve fibre layer defects in glaucomatous eyes.

BACKGROUND/AIMS: Evaluation of the retinal nerve fibre layer (RNFL) is important for identifying glaucomatous damage. Ultrawide-field fundus photography (UWP) imaging is increasingly used in the ophthalmological field; however, it is unknown whether it can be used for detecting RNFL defects (RNFLDs). We investigated whether RNFLD can be detected with UWP images and compared the clinical effectiveness of three types of images for detecting RNFLD: conventional red-free RNFL photography (RFP), non-mydriatic UWP and digitally converted green separation of non-mydriatic UWP (G-UWP). METHODS: Eyes with glaucoma or glaucoma suspect and normal control eyes meeting the eligibility criteria were consecutively enrolled from September 2019 to April 2020. Their conventional RFP, non-mydriatic UWP and G-UWP images were assessed for detecting RNFLD to evaluate the sensitivity and specificity for detecting RNFLD. RESULTS: Three image sets of 196 participants (84 normal control, 25 glaucoma suspect and 87 glaucoma) were obtained. The sensitivity of G-UWP (94.6%; 95% CI 88.7 to 98.0) and RFP (92.9%; 95% CI 86.4 to 96.9) was higher than that of UWP (82.1%; 95% CI 73.8 to 88.7; p<0.05). The sensitivities of G-UWP and RFP are comparable. The specificity of G-UWP (78.6%; 95% CI 68.3 to 86.8) and UWP (75.0%; 95% CI 64.4 to 83.8) was comparable, but both were lower than that of RFP (98.8%; 95% CI 93.5 to 100.0; p<0.05). CONCLUSION: Non-mydriatic UWP images can be used to detect RNFLD. Non-mydriatic G-UWP showed comparable sensitivity but lower specificity to conventional RFP. Non-mydriatic G-UWP could be used as a convenient and useful diagnostic tool for screening glaucoma in clinical settings.

Selective Laser Trabeculoplasty for Medically Uncontrolled Pseudoexfoliation Glaucoma in Korean Patients.

PURPOSE: This study investigated the efficacy and safety of selective laser trabeculoplasty (SLT) in Korean patients with medically uncontrolled pseudoexfoliation glaucoma (PEXG). METHODS: This retrospective observational study enrolled 43 medically uncontrolled PEXG patients who underwent a 360° SLT and were followed up for at least 12 months after SLT. The intraocular pressure (IOP) before and after SLT at 1 week, 1, 3, 6, and 12 months was evaluated. Treatment success was defined as an IOP reduction of ≥20% from the baseline and an IOP equal to lower than 22 mmHg without additional anti-glaucomatous intervention. Additionally, every follow-up medical record was reviewed to assess any possible side effects of SLT. RESULTS: Based on the Kaplan-Meier survival analysis, the treatment success rate at 12 months after SLT was 41.9% (18 eyes). For the success group at the 12 months follow-up, SLT showed a mean IOP reduction of 10.3 ± 5.0 mmHg (from 25.6 ± 4.4 to 15.2 ± 2.9 mmHg; 39.3%, p < 0.05). Among the 25 eyes that were considered as the treatment failure group, 14 eyes underwent glaucoma filtering surgeries, four eyes received additional SLT, and further intervention and follow-up was refused for seven eyes. During the overall follow-up period, there were no significant adverse events. CONCLUSIONS: SLT is a partially effective and safe procedure for lowering IOP in Korean patients with medically refractory PEXG. Therefore, it can be considered as one of the alternative treatment modalities in patients who are at high risk for conventional filtering surgery.

Effect of Anti-glaucoma Agents on Myopic Retinoschisis.

PURPOSE: To evaluate the effect of intraocular pressure (IOP)-lowering medications on myopic retinoschisis. METHODS: The medical records of 33 patients (36 eyes) with myopic retinoschisis associated with pathologic myopia were reviewed retrospectively. The patients were divided into two groups: the study group comprising patients undergoing treatment with anti-glaucoma medications for suspected glaucoma; the control group comprising patients who did not use any IOP lowering medications. The changes in retinoschisis in the two groups were compared using the Spectralis domain optical coherence tomography thickness map protocol. RESULTS: The study group included 18 eyes (17 patients), and the control group included 18 eyes (16 patients). There were no significant differences between the 6-month and 12-month improvement or aggravation rates of the two groups (p = 0.513 and 0.137, respectively). However, after 18 months, the aggravation rate of retinoschisis was significantly lower in the study group (p = 0.003). The improvement / aggravation rate was 58.33% / 16.67% in the study group and 0% / 57.14% in the control group. CONCLUSIONS: The use of IOP-lowering medications for more than a year may be useful for the management of retinoschisis associated with pathologic myopia.

Mucoadhesive microparticles with a nanostructured surface for enhanced bioavailability of glaucoma drug.

Topical drug administration to the eye is limited by low drug bioavailability due to its rapid clearance from the preocular surface. Thus, multiple daily administrations are often needed, but patient compliance is low, hence a high chance of unsatisfactory treatment of ocular diseases. To resolve this, we propose mucoadhesive microparticles with a nanostructured surface as potential carriers for delivery of brimonidine, an ocular drug for glaucoma treatment. For sustained drug delivery, the microparticles were composed mainly of a diffusion-wall material, poly(lactic-co-glycolic acid) and a mucoadhesive polymer, polyethylene glycol, was used as an additive. Due to their nanostructured surface, the microparticles with a mucoadhesive material exhibited a 13-fold increase in specific surface area and could thus adhere better to the mucous layer on the eye, as compared with the conventional spherical microparticles. When loaded with brimonidine, the mucoadhesive microparticles with a nanostructured surface increased both drug bioavailability and its activity period by a factor of more than 2 over Alphagan P, a marketed eye drop of brimonidine.

Preliminary study on implantable inductive-type sensor for continuous monitoring of intraocular pressure.

BACKGROUND: This study aims to validate the performance and biocompatibility of an implantable inductive-type sensor for continuous monitoring of intraocular pressure (IOP) METHODS: The sensor is composed of a top layer integrated with an inductor and capacitor circuit, and a bottom layer integrated with ferrite. With IOP change, the sensor's bottom layer is mechanically deflected, which changes the distance between the bottom-layer ferrite and top-layer inductor, resulting in an alteration of inductance magnitude and the resonant frequency (RF). In-vitro measurement was conducted via air pressurization in a sealing jig (n = 3). Subsequently, the sensor was implanted into the anterior chamber of a rabbit eye. In-vivo measurement was performed while the IOP was elevated by infusion of balanced salt solution (BSS, 6 µL/min). Smaller-sized sensors later were implanted into two rabbit eyes, which were microscopically examined at 2, 4 and 8 weeks post-implantation. The eyes were then immediately enucleated for histological examination. RESULTS: The in-vitro measurement showed a significant RF shift as pressure in the jig was increased from 0 mmHg to 60 mmHg (average initial frequency: 10.86 MHz, average shift: 403 kHz). The in-vivo measurement also showed an RF decrease, from 12.80 MHz to 12.67 MHz, as the pressure was increased from 10 mmHg to 20 mmHg. Microscopic in-vivo evaluations and histological exams, performed at intervals up to 8 weeks post-implantation, showed no evidence of significant inflammation or deformity of the ocular-tissue structures. CONCLUSIONS: The implantable inductive-type IOP sensor demonstrated wireless pressure-sensing ability and favourable biocompatibility in the rabbit eye.

Comparison of macular GCIPL and peripapillary RNFL deviation maps for detection of glaucomatous eye with localized RNFL defect.

PURPOSE: To evaluate the ability of the deviation map of macular ganglion cell-inner plexiform layer (GCIPL) thickness compared with that of peripapillary retinal nerve fibre layer (pRNFL) thickness for detection of localized RNFL defects shown on red-free RNFL photography. METHODS: This prospective cross-sectional study included 69 eyes of 69 subjects with preperimetric or perimetric glaucoma (mean deviation (MD) >-12dB) and localized RNFL defects along with 79 eyes of 79 normal control subjects. The number of abnormal superpixels on the both macular GCIPL and pRNFL deviation maps by Cirrus OCT corresponding to localized RNFL defects was calculated using a customized Matlab program and presented as severity indices according to each of the probability levels. The areas under the receiver operating characteristic curves (AUROCs) of the severity indices were compared between the two deviation maps. RESULTS: According to three criteria and corresponding probability levels, the AUROCs of the GCIPL and pRNFL deviation maps ranged from 0.910 to 0.931 and 0.934 to 0.950, respectively. However, the differences were not statistically significant (all p > 0.05). Significant correlations were observed between the severity indices of the GCIPL deviation map and those of the pRNFL deviation map, regardless of the criteria (all p < 0.0001). CONCLUSIONS: In the detection of glaucomatous eyes with localized RNFL defects, the macular GCIPL thickness deviation map showed a level of diagnostic performance comparable to that of the pRNFL thickness deviation map.

Novel screening method for glaucomatous eyes with myopic tilted discs: the crescent moon sign.

IMPORTANCE: To our knowledge, there is no reliable screening method for glaucomatous eyes with myopic tilted discs. OBJECTIVE: To evaluate the diagnostic ability of a novel screening modality, the crescent moon (CM) sign, defined as the discontinuity between the superior or inferior optic rim margin and the temporal optic rim margin, for the detection of glaucomatous eyes with myopic tilted discs. DESIGN, SETTING, AND PARTICIPANTS: The study was cross-sectional and conducted in a hospital setting from November 1, 2011, to November 1, 2013. Seventy eyes of 70 individuals with early open-angle glaucoma (mean deviation greater than -6 dB) and 70 eyes of 70 normal control participants who had myopic tilted discs were recruited. Another independent group consisting of 60 eyes of 60 individuals with early glaucoma and 60 eyes of 60 normal control participants was enrolled. Two masked glaucoma specialists independently assessed the optic disc on stereoscopic disc photography. The diagnostic performance of the CM sign was evaluated in comparison with violation of the ISNT rule (inferior ≥ superior ≥ nasal ≥ temporal order of configuration for disc rim thickness in normal eyes) and the modified ISNT rule (application of the ISNT rule based on the long axis of the disc). MAIN OUTCOMES AND MEASURES: Sensitivity and specificity of the CM sign. RESULTS: The CM sign was more frequently observed in the inferotemporal optic rim margin than in the superotemporal optic rim margin. In a comparative evaluation of the glaucoma diagnostic sensitivity and specificity, the CM sign showed higher sensitivities (90.0%-91.4%) than the ISNT rule (73.3%-75.7%) or the modified ISNT rule (68.6%-70.0%). The CM sign also showed higher specificities (82.9%-83.3%) than the ISNT rule (68.3%-71.4%) or the modified ISNT rule (76.6%-80.0%). Furthermore, the CM sign was shown to be associated with the occurrence of visual field defects in the corresponding hemifield (P < .001). CONCLUSIONS AND RELEVANCE: The CM sign can be a useful screening tool for the detection of early glaucoma with myopic tilted discs.

Risk factors for open-angle glaucoma with normal baseline intraocular pressure in a young population: the Korea National Health and Nutrition Examination Survey.

BACKGROUND: To identify risk factors associated with open-angle glaucoma with normal baseline intraocular pressure in a young Korean population. DESIGN: Retrospective, population-based, case-control study. PARTICIPANTS: Between 2009 and 2010, among participants from the Korea National Health and Nutrition Examination Survey (n = 17 901), subjects between 19 and 39 years of age were included. METHODS: Participants had structured interviews systemic and ophthalmic examination. Glaucoma was diagnosed using the International Society of Geographical and Epidemiological Ophthalmology criteria. MAIN OUTCOME MEASURES: The risk factors for open-angle glaucoma with normal baseline intraocular pressure were analyzed using univariate and multivariate comparisons. RESULTS: Eighty open-angle glaucoma with normal baseline intraocular pressure patients and 4015 controls were included. In the univariate analysis, the patient group was more likely to have higher fasting plasma glucose (98.04 ± 33.16 vs. 89.74 ± 12.65, P < 0.001) and higher proportion of fasting capillary glucose ≥200 mg/dL (P < 0.001) than the control. Multivariate analysis found that high myopia (odds ratio, 3.54 [95% confidence interval, 1.34-9.39], P = 0.011), fasting capillary glucose ≥200 mg/dL (odds ratio, 12.65 [95% confidence interval, 2.63-60.94], P = 0.002) and low high-density lipoprotein cholesterol (odds ratio, 0.96 [95% confidence interval, 0.94-0.99], P = 0.015) were associated with an increased risk of having open-angle glaucoma with normal baseline intraocular pressure. CONCLUSIONS: High myopia, fasting capillary glucose level ≥200 mmol/L and high-density lipoprotein cholesterol level were significant risk factors for open-angle glaucoma with normal baseline intraocular pressure in a young Korean population.

Topographic profiles of retinal nerve fiber layer defects affect the diagnostic performance of macular scans in preperimetric glaucoma.

PURPOSE: To evaluate the influence of topographic profiles (i.e., inner directional angle and angular width) of localized retinal nerve fiber layer (RNFL) defects on the diagnostic performance of macular ganglion cell-inner plexiform layer (GCIPL) thickness in discriminating preperimetric glaucoma (PPG) eyes from normal control eyes. METHODS: The ganglion cell analysis algorithm in Cirrus OCT was performed to determine the macular GCIPL thickness. Areas under the receiver operating characteristic curves (AUROCs) and the sensitivities/specificities based on an internal normative database were evaluated. The effect of the inner directional angle and the angular width of localized RNFL defects on the diagnostic performance of macular GCIPL parameters were evaluated by using linear-by-linear association analysis and logistic regression analysis. RESULTS: Ninety-two patients with PPG and 92 age-matched healthy control subjects were enrolled in this study. The AUROC of the best parameters in macular GCIPL was 0.823 (inferotemporal sector), which showed no significant difference in comparison to the best parameters of peripapillary RNFL (7 o'clock sector, 0.764) and optic nerve head (rim area, 0.767) (for all comparisons, P > 0.05). A significant linear association was observed between the inner directional angle of RNFL defects and the sensitivity of macular GCIPL parameters for detecting RNFL defects. The angular width of RNFL defects was not significantly associated with the sensitivity of macular GCIPL parameters. CONCLUSIONS: The diagnostic ability of macular GCIPL parameters was comparable to that of peripapillary RNFL and ONH parameters in PPG. The inner directional angle of RNFL defects, but not the angular width, affects the diagnostic sensitivity of macular GCIPL parameters.

The distribution of intraocular pressure and associated systemic factors in a Korean population: the Korea National Health and Nutrition Examination Survey.

PURPOSE: To investigate the distribution of intraocular pressure (IOP) and its associated factors in a large Korean population based on the data from the nationwide cross-sectional survey. METHODS: We obtained 2009-2010 data from the Korea National Health and Nutrition Examination Survey (KNHANES) (n = 17 901). After excluding individuals under 19 years of age, a total of 13 431 subjects were enrolled. All participants completed a comprehensive questionnaire and underwent an ocular examination including measurement of IOP by Goldmann applanation tonometry, as well as a systemic evaluation including blood pressure measurements, anthropometry and blood tests. RESULTS: The mean IOP in the right eye was 13.99 ± 2.75 mmHg, and in the left eye, 13.99 ± 2.75 mmHg, representing no significant bilateral difference. There was, however, a significant difference between males (14.19 ± 2.78 mmHg) and females (13.79 ± 2.70 mmHg) (p < 0.001). Multiple regression analysis revealed that higher IOP was significantly correlated with male sex, higher myopic refractive error, higher body mass index, higher systolic blood pressure, higher fasting plasma glucose and higher total cholesterol (all p < 0.05). On the other hand, age, histories of smoking or migraine or cold hands/feet were not significantly correlated with IOP (all p > 0.05). CONCLUSIONS: In the general Korean population, IOP increases with male sex and increasing myopia. Further, IOP is significantly correlated with systemic factors relating to cardiovascular disease and metabolic syndrome.

Nanostructured mucoadhesive microparticles for enhanced preocular retention.

We describe nanostructured microparticles (NMs) containing a mucoadhesive polymer for enhanced preocular retention and consider them as potential carriers of drugs to the eye. These NMs are each composed of entangled nanofibers to give an enlarged specific surface area, and thus can better adhere to the preocular mucus surface. This physical design allows the microparticles still to be composed mainly of a wall material, poly(lactic-co-glycolic acid), as required for controlled drug delivery, while the effects of an additive, mucoadhesive material, polyethylene glycol, can be synergistically improved via the nanostructured morphology. Thus, when formulated in a dry tablet dosage form, the NMs in this work show more than a 10-fold increase in preocular retention in vivo compared to conventional spherical microparticles. Therefore, we conclude that these mucoadhesive NMs can reside on the preocular surface for a prolonged period, and thus appear to be a promising system for topical drug delivery to the eye.

Comparison of localized retinal nerve fiber layer defects in highly myopic, myopic, and non-myopic patients with normal-tension glaucoma: a retrospective cross-sectional study.

BACKGROUND: The purpose of this study was to evaluate the relationship between patterns of localized retinal nerve fiber layer (RNFL) defects and the degree of myopia in patients with normal-tension glaucoma (NTG). METHODS: We retrospectively reviewed medical records of patients with high myopia (42 eyes; spherical equivalent [SE] < -6.0 diopters [D]), low to moderate myopia (93 eyes; SE -6.0D ~ and -0.5D), and emmetropia (65 eyes; SE -0.5D ~ +0.5D), all of which were diagnosed as having NTG with localized RNFL defects. On RNFL photographs, the proximity of the RNFL defect to the center of the fovea (angle I) and the sum of the angular width of the defects (angle II) were determined. The patterns of localized RNFL defects were then compared with respect to differences in angles I and II. RESULTS: Angle I was significantly smaller in the high myopia group than in the low to moderate myopia group (p = 0.028) and the emmetropia group (p = 0.044), while angle II was significantly larger in the high myopia group compared with the low to moderate myopia group and the emmetropia group (p < 0.001, p = 0.007). CONCLUSIONS: Among subjects with NTG, localized RNFL defects are wider and closer to the fovea in eyes with high myopia than those with low to moderate myopia or emmetropia.

CD49f(high) cells retain sphere-forming and tumor-initiating activities in human gastric tumors.

Identification of gastric tumor-initiating cells (TICs) is essential to explore new therapies for gastric cancer patients. There are reports that gastric TICs can be identified using the cell surface marker CD44 and that they form floating spheres in culture, but we could not obtain consistent results with our patient-derived tumor xenograft (PDTX) cells. We thus searched for another marker for gastric TICs, and found that CD49f(high) cells from newly-dissected gastric cancers formed tumors with histological features of parental ones while CD49f(low) cells did not when subcutaneously injected into immunodeficient mice. These results indicate that CD49f, a subunit of laminin receptors, is a promising marker for human gastric TICs. We established a primary culture system for PDTX cells where only CD49f(high) cells could grow on extracellular matrix (ECM) to form ECM-attaching spheres. When injected into immunodeficient mice, these CD49f(high) sphere cells formed tumors with histological features of parental ones, indicating that only TICs could grow in the culture system. Using this system, we found that some sphere-forming TICs were more resistant than gastric tumor cell lines to chemotherapeutic agents, including doxorubicin, 5-fluorouracil and doxifluridine. There was a patient-dependent difference in the tumorigenicity of sphere-forming TICs and their response to anti-tumor drugs. These results suggest that ECM plays an essential role for the growth of TICs, and that this culture system will be useful to find new drugs targeting gastric TICs.

Resolution of recalcitrant uveitic optic disc edema following administration of methotrexate: two case reports.

A 13-year-old male and a 15-year-old female presented with optic disc edema associated with chronic recurrent uveitis. While the ocular inflammation responded to high doses of oral prednisolone, the disc edema showed little improvement. After oral administration of methotrexate, the disc edema and ocular inflammation were resolved, and the dose of oral corticosteroid could be reduced.

Long-term follow-up of changes in corneal endothelium after primary and secondary intraocular lens implantations in children.

BACKGROUND: To evaluate long-term changes in corneal endothelial cell count and morphology after congenital cataract extraction and intraocular lens implantation. METHODS: Cataract extraction and posterior chamber intraocular lens (IOL) implantation was performed on 54 congenital cataract patients (83 eyes). The corneal endothelial cell density (ECD), coefficient of variation (CV), hexagonality, and central corneal thickness (CCT) were measured for a retrospective analysis of long-term changes in corneal endothelial characteristics. RESULTS: The mean age at the time of IOL implantation was 5.00 (3.62) years [mean (SD)], and the mean follow-up period was 8.83 (1.49) years. In a comparison of the treated and normal eyes of patients who underwent unilateral surgery, the treated eyes showed a significantly greater CCT (p < 0.05), and there was no significant difference in ECD, CV, and hexagonality (p > 0.05). In addition, there was no statistically significant difference in the ECD and CCT between the primary and secondary IOL implantation groups. CONCLUSIONS: Our results did not show any significant corneal endothelial cell loss in congenital cataract patients; however, their CCTs were increased.