Automated macular segmentation can distinguish glaucomatous from compressive optic neuropathy.

PURPOSE: To compare macular damage in glaucomatous optic neuropathy (GON) and compressive optic neuropathy (CON) and assess its diagnostic accuracy in distinguishing between diseases. METHODS: Observational, cross-sectional, single-center study. Patients with GON, CON, and healthy controls were included according to the eligibility criteria. An automated spectral-domain optical coherence tomography (SD-OCT) algorithm was used to segment the circumpapilary retinal nerve fiber layer (cpRNFL) and macula. The layer thickness was measured in each sector according to the Early Treatment Diabetic Retinopathy Study and the 6-sector Garway-Heath-based grids. Data was compared across all study groups, and the significance level was set at 0.05. RESULTS: Seventy-five eyes of 75 participants, 25 with GON, 25 with CON, and 25 healthy controls (CG), were included. Macular thickness was diminished in the ganglion cell complex of GON and CON patients compared to CG (p<0.05). The best Garway-Heath-based grid parameters for distinguishing GON and CON were the nasal-inferior (NI) and nasal-superior sectors and the NI/temporal inferior (TI) damage ratios in the macular ganglion cell (mGCL) and inner plexiform (IPL) layers. Moreover, the combination of the NI sector and NI/TI damage ratios in both layers had higher discriminative power (AUC 0.909; 95% CI 0.830-0.988; p<0.001) than combining parameters in each layer separately. CONCLUSION: Our findings suggest that the evaluation of macular segmented layers damage by SD-OCT may be a helpful add-on tool in the differential diagnosis between GON and CON.

Comparison of the retinal microvasculature between compressive and glaucomatous optic neuropathy.

PURPOSE: To compare the patterns of retinal microvasculature change in the peripapillary and macular region between compressive optic neuropathy (CON) and glaucomatous optic neuropathy (GON), and to assess the ability of optical coherence tomography angiography (OCTA) in differentiating the two conditions. METHODS: This cross-sectional study included 108 participants (108 eyes), 36 with CON, 36 with GON, and 36 healthy controls. The CON and GON eyes were matched by the average peripapillary retinal nerve fiber layer (pRNFL) thickness (1:1). Optical coherence tomography (OCT) and OCTA were performed to compare the structural and vascular change of the peripapillary and macular region between groups. RESULTS: Both CON and GON eyes showed more severe structural and vascular damage than the control eyes. The CON eyes had lower pRNFL thickness than the GON eyes in the temporal and nasal quadrants, and thicker pRNFL thickness in the inferior quadrant. The average GCC thickness did not differ between the two groups. The peripapillary vessel density of the CON group was significantly higher in the inferior sectors than that of the GON group. In the macular region, the CON group had significantly higher vessel density in the whole image, the temporal sector in parafovea region, and the temporal, superior, and inferior sectors in perifovea region. CONCLUSION: To a similar degree of structural damage, CON had less retinal vascular impairment than GON, especially in the macular region, and the significance of the finding needs further evaluation.

Neuroprotective effects of idebenone on hydrogen peroxide-induced oxidative damage in retinal ganglion cells-5.

PURPOSE: To investigate the neuroprotective effect of idebenone against hydrogen peroxide (H2O2)-induced oxidative damage in retinal ganglion cells-5 (RGC-5 cells). METHODS: RGC-5 cells were pre-treated with various idebenone concentrations (5, 10, and 20 µM) for 12 h and were then subjected to 300 µM H2O2 for a further 12 h. Apoptosis in RGC-5 was measured by flow cytometry. The changes of mitochondrial membrane potential (MMP) were detected by JC-1 staining. Autophagy in RGC-5 cells was observed by transmission electron microscopy. Western blots were used to measure the expression of autophagy-related protein light chain 3 (LC3), Beclin-1, and the release of Cytochrome c (Cyt-c). RESULTS: Flow cytometry showed that the apoptosis rates in the normal control group, H2O2 group, and idebenone groups were 6.48 ± 0.55%, 27.3 ± 0.51%, 22.8 ± 0.52%, 15.45 ± 0.81%, and 12.59 ± 0.58%, respectively (F = 559.7, P < 0.0001). After incubation with H2O2, the number of autophagosomes increased significantly, whereas it was decreased in the idebenone groups. After incubation of RGC-5 cells with H2O2, MMP levels were significantly decreased, while idebenone could prevent the decrease in MMP levels. Compared with that in the normal control group, LC3 II/I, the expression levels of Beclin-1 and Cyt-c were increased significantly in the H2O2 group (P < 0.05). Compared with that in the H2O2 group, LC3 II/I, the expression of Beclin-1 and Cyt-c was significantly decreased in idebenone groups (P < 0.05). CONCLUSIONS: Idebenone protects RGC-5 cells against H2O2-induced oxidative damage by reducing mitochondrial damage and autophagic activity.

Multimodal Machine Learning Using Visual Fields and Peripapillary Circular OCT Scans in Detection of Glaucomatous Optic Neuropathy.

PURPOSE: To develop and validate a multimodal artificial intelligence algorithm, FusionNet, using the pattern deviation probability plots from visual field (VF) reports and circular peripapillary OCT scans to detect glaucomatous optic neuropathy (GON). DESIGN: Cross-sectional study. SUBJECTS: Two thousand four hundred sixty-three pairs of VF and OCT images from 1083 patients. METHODS: FusionNet based on bimodal input of VF and OCT paired data was developed to detect GON. Visual field data were collected using the Humphrey Field Analyzer (HFA). OCT images were collected from 3 types of devices (DRI-OCT, Cirrus OCT, and Spectralis). Two thousand four hundred sixty-three pairs of VF and OCT images were divided into 4 datasets: 1567 for training (HFA and DRI-OCT), 441 for primary validation (HFA and DRI-OCT), 255 for the internal test (HFA and Cirrus OCT), and 200 for the external test set (HFA and Spectralis). GON was defined as retinal nerve fiber layer thinning with corresponding VF defects. MAIN OUTCOME MEASURES: Diagnostic performance of FusionNet compared with that of VFNet (with VF data as input) and OCTNet (with OCT data as input). RESULTS: FusionNet achieved an area under the receiver operating characteristic curve (AUC) of 0.950 (0.931-0.968) and outperformed VFNet (AUC, 0.868 [95% confidence interval (CI), 0.834-0.902]), OCTNet (AUC, 0.809 [95% CI, 0.768-0.850]), and 2 glaucoma specialists (glaucoma specialist 1: AUC, 0.882 [95% CI, 0.847-0.917]; glaucoma specialist 2: AUC, 0.883 [95% CI, 0.849-0.918]) in the primary validation set. In the internal and external test sets, the performances of FusionNet were also superior to VFNet and OCTNet (FusionNet vs VFNet vs OCTNet: internal test set 0.917 vs 0.854 vs 0.811; external test set 0.873 vs 0.772 vs 0.785). No significant difference was found between the 2 glaucoma specialists and FusionNet in the internal and external test sets, except for glaucoma specialist 2 (AUC, 0.858 [95% CI, 0.805-0.912]) in the internal test set. CONCLUSIONS: FusionNet, developed using paired VF and OCT data, demonstrated superior performance to both VFNet and OCTNet in detecting GON, suggesting that multimodal machine learning models are valuable in detecting GON.

The Role of miR-29 Family in TGF-ß Driven Fibrosis in Glaucomatous Optic Neuropathy.

Primary open angle glaucoma (POAG), a chronic optic neuropathy, remains the leading cause of irreversible blindness worldwide. It is driven in part by the pro-fibrotic cytokine transforming growth factor beta (TGF-ß) and leads to extracellular matrix remodelling at the lamina cribrosa of the optic nerve head. Despite an array of medical and surgical treatments targeting the only known modifiable risk factor, raised intraocular pressure, many patients still progress and develop significant visual field loss and eventual blindness. The search for alternative treatment strategies targeting the underlying fibrotic transformation in the optic nerve head and trabecular meshwork in glaucoma is ongoing. MicroRNAs are small non-coding RNAs known to regulate post-transcriptional gene expression. Extensive research has been undertaken to uncover the complex role of miRNAs in gene expression and miRNA dysregulation in fibrotic disease. MiR-29 is a family of miRNAs which are strongly anti-fibrotic in their effects on the TGF-ß signalling pathway and the regulation of extracellular matrix production and deposition. In this review, we discuss the anti-fibrotic effects of miR-29 and the role of miR-29 in ocular pathology and in the development of glaucomatous optic neuropathy. A better understanding of the role of miR-29 in POAG may aid in developing diagnostic and therapeutic strategies in glaucoma.

[Use and outcomes of antioxidant therapy in ophthalmic practice]. / Vozmozhnosti i rezul'taty primeneniya antioksidantnoi terapii v oftal'mologicheskoi praktike.

Advances in medical diagnostic technologies, particularly in ophthalmology, help researchers understand histological characteristics of the human eye and study vision at the cellular level. In addition to its role in the ocular function associated with the control of movements, senses and protective responses, the nervous system plays a key role in regulation of the visual process. Neurodegenerative disorders hold a special place among systemic diseases. Presently, the development of such pathologies are associated with neuroinflammation, which has been proven to also contribute to the glaucomatous process. For this reason, achieving target intraocular pressure does not always guarantee stabilization of the degenerative process. In this context, neuroprotective agents are recommended for glaucoma management to all patients taking into consideration pathogenetic characteristics of the disease. Based on its antioxidative and neuroprotective effects, ethylmethylhydroxypyridine succinate (Mexidol) is commonly used in ophthalmic practice, specifically in the treatment of patients with glaucomatous optic neuropathy and retinal diseases. The results of studies demonstrate that Mexidol is effective in slowing down neurodegeneration and stabilizing visual functions in patients with primary open-angle glaucoma due to its antihypoxic, antioxidant and membrane-stabilizing properties, as well as its positive impact on the neuromediator balance and ocular blood flow.

[Current trends in studying pathogenesis of glaucoma]. / Sovremennye napravleniya v izuchenii patogeneza pervichnoi glaukomy.

Glaucoma is a group of neurodegenerative disorders comprising one of the main causes of irreversible blindness. Glaucoma-related blindness is a globally relevant problem. By now, many aspects of glaucoma pathogenesis have been studied: impact of increased intraocular pressure (IOP) on the development of optic neuropathy, ischemia and reperfusion of the retina, most of the direct mechanisms of neuronal death (excitotoxicity, oxidative stress, etc). However, the only effective glaucoma treatment is lowering the IOP, while early glaucoma diagnosis is based on determining structural and functional retinal defects. Therefore, it is important to emphasize further research on the insufficiently studied aspects of glaucoma pathogenesis - such as neuroinflammation, translaminar pressure, genetic factors, association of glaucomatous damage with changes in the brain, mitochondrial pathologies, and others. The article reviews the most perspective directions in research of the pathogenesis of glaucomatous optic neuropathy.

Deep learning-based automated detection of glaucomatous optic neuropathy on color fundus photographs.

PURPOSE: To develop a deep learning approach based on deep residual neural network (ResNet101) for the automated detection of glaucomatous optic neuropathy (GON) using color fundus images, understand the process by which the model makes predictions, and explore the effect of the integration of fundus images and the medical history data from patients. METHODS: A total of 34,279 fundus images and the corresponding medical history data were retrospectively collected from cohorts of 2371 adult patients, and these images were labeled by 8 glaucoma experts, in which 26,585 fundus images (12,618 images with GON-confirmed eyes, 1114 images with GON-suspected eyes, and 12,853 NORMAL eye images) were included. We adopted 10-fold cross-validation strategy to train and optimize our model. This model was tested in an independent testing dataset consisting of 3481 images (1524 images from NORMAL eyes, 1442 images from GON-confirmed eyes, and 515 images from GON-suspected eyes) from 249 patients. Moreover, the performance of the best model was compared with results obtained by two experts. Accuracy, sensitivity, specificity, kappa value, and area under receiver operating characteristic (AUC) were calculated. Further, we performed qualitative evaluation of model predictions and occlusion testing. Finally, we assessed the effect of integrating medical history data in the final classification. RESULTS: In a multiclass comparison between GON-confirmed eyes, GON-suspected eyes and NORMAL eyes, our model achieved 0.941 (95% confidence interval [CI], 0.936-0.946) accuracy, 0.957 (95% CI, 0.953-0.961) sensitivity, and 0.929 (95% CI, 0.923-0.935) specificity. The AUC distinguishing referrals (GON-confirmed and GON-suspected eyes) from observation was 0.992 (95% CI, 0.991-0.993). Our best model had a kappa value of 0.927, while the two experts' kappa values were 0.928 and 0.925 independently. The best 2 binary classifiers distinguishing GON-confirmed/GON-suspected eyes from NORMAL eyes obtained 0.955, 0.965 accuracy, 0.977, 0.998 sensitivity, and 0.929, 0.954 specificity, while the AUC was 0.992, 0.999 respectively. Additionally, the occlusion testing showed that our model identified the neuroretinal rim region, retinal nerve fiber layer (RNFL) defect areas (superior or inferior) as the most important parts for the discrimination of GON, which evaluated fundus images in a way similar to clinicians. Finally, the results of integration of fundus images with medical history data showed a slight improvement in sensitivity and specificity with similar AUCs. CONCLUSIONS: This approach could discriminate GON with high accuracy, sensitivity, specificity, and AUC using color fundus photographs. It may provide a second opinion on the diagnosis of glaucoma to the specialist quickly, efficiently and at low cost, and assist doctors and the public in large-scale screening for glaucoma.

Long segment 3D double inversion recovery (DIR) hypersignal on MRI in glaucomatous optic neuropathy.

BACKGROUND: In this retrospective study the relationship between intraocular pressure (IOP), retinal nerve fiber layer (RNFL) thickness and pathologic hypersignal in optic nerve segments on 3D double inversion recovery (DIR) MR sequence in 21 patients with proven glaucoma of different origin was evaluated. METHODS: All patients were examined on a 3 T MR Philips® scanner. Pathologic optic nerve DIR hypersignal was determined in four different nerve segments. IOP was measured in mmHg by applanation tonometry. RNFL thickness was measured in µm with optical coherence tomography (OCT Heidelberg Engineering Spectralis® apparatus). Wilcoxon rank sum tests, student's t-tests and (multivariate) linear regression models were appied. RESULTS: 3D DIR hypersignal was present in 17 (41.5%) optic nerves. 3D DIR hypersignal was not related to ischemic or demyelinating optic nerve pathology but was associated with increased IOP (19.8 [24-18]; versus 15.45; [18.85-13.75] mmHg; p = 0.008) and decreased RNFL thickness (61.06 ± 12.1 versus 82.5 ± 21.6 µm; p < 0.001) in comparison to optic nerves of glaucoma patients without DIR hypersignal. Specifically, presence of DIR hypersignal in optic nerves in at least one optic nerve segment lowered RNFL thickness on average by 17.54 µm (p = 0.005) in comparison to optic nerves without DIR hypersignal. CONCLUSIONS: In patients with glaucomatous optic neuropathy (GON) and pathologic optic nerve DIR hypersignal, significantly increased IOP and significantly decreased RNFL thickness values are present. DIR hypersignal seems to be a marker for disease severity in GON related to decreased RNFL thickness and may thus represent long-segment severe axonal degeneration in optic nerves in patients with GON. Venous congestion and edema within the optic nerve related to high IOP may contribute to the DIR hypersignal as well.

[Modern view on ocular hypertension]. / Sovremennyi vzgliad na problemu oftal'mogipertenzii.

Increased intraocular pressure is the main, and the only modifiable risk factor in the development of glaucoma. This review analyzes studies on differential diagnostics of ocular hypertension and risk factors of its conversion to glaucoma, and gives recommendations based on literature data for the most correct algorithm for management of patients with ocular hypertension.

Macular retinoschisis in eyes with glaucomatous optic neuropathy: Vitrectomy and natural course.

PURPOSE: Our purpose was to determine the effectiveness of vitrectomy in resolving the macular retinoschisis in an eye with glaucomatous optic neuropathy and also to determine the natural course of macular retinoschisis. METHODS: This was a retrospective case series of patients who were diagnosed with macular retinoschisis and glaucomatous optic neuropathy. Fourteen eyes of 13 patients were studied. Patients with high myopia, vitreomacular traction syndrome, and the pit macular syndrome were excluded. RESULTS: There were three men and ten women, and 12 had unilateral and one had bilateral macular retinoschisis. Vitrectomy was performed for a serous retinal detachment, macular hole, or severe visual loss in five eyes. The mean follow-up time was 68.8 months in these five eyes, and the macular retinoschisis was resolved and the best-corrected visual acuity (BCVA) at the final visit was significantly improved in all eyes (P = 0.007). However, two of these fiv e eyes developed a macular hole and required a second vitrectomy. Of the nine eyes without treatment with a mean follow-up time of 29.0 months, the BCVA at the final visit remained unchanged from the baseline BCVA in all eyes. The macular retinoschisis was resolved or reduced in three eyes without treatment. CONCLUSIONS: Vitrectomy was effective for the resolution of macular retinoschisis in eyes with glaucomatous optic neuropathy and serous retinal detachment or macular hole or severe reduction of the BCVA. Macular retinoschisis can be resolved without a reduction of the BCVA in some cases without treatment.

Diagnostic performance of isolated-check visual evoked potential versus retinal ganglion cell-inner plexiform layer analysis in early primary open-angle glaucoma.

BACKGROUND: The purpose of this study was to compare the diagnostic performance of isolated-check visual evoked potential (icVEP) with that of retinal ganglion cell-inner plexiform layer (GCILP) analysis using optical coherence tomography (OCT). METHODS: A total of 45 patients were enrolled: 25 patients with open-angle glaucoma and 20 healthy patients. All patients underwent a complete ophthalmological examination. Moreover, the OCT examination was used to analyze the structures of the GCIPL. The icVEP technique was used to detect the transmission function of the magnocellular pathway, which is mainly managed by the retinal ganglion cells. The quantitative and qualitative comparisons between the diagnostic power of GCIPL analysis and that of icVEP were performed. The areas under the receiver operating characteristic curves (AUC) of GCIPL analysis and icVEP were compared using the Clarke-Pearson method. The sensitivity and specificity of the two techniques were analyzed and compared using the McNemar test. RESULTS: With the quantitative comparison, the AUC of icVEP (AUC = 0.892) was higher than that of GCIPL analysis (AUC = 0.814). However, there was no statistical significance between the AUCs of icVEP and GCIPL (P > 0.05). With the qualitative comparison, the sensitivity of icVEP was 80%, and its specificity was 90%. The sensitivity of GCIPL analysis was 72%, and its specificity was 85%. There was no significant difference between the sensitivitiesor specificities of icVEP and GCIPL analysis (P > 0.05). Moreover, 30 (66.67%) eyeshad similar resultsbetween icVEP and GCIPL analysis, and 15 (33.33%) eyes had different results (7 eyes had abnormal results with GCIPL analysisbut normal results with icVEP, and8 eyes had normal results with GCIPL analysisbut abnormal results with icVEP). CONCLUSIONS: The diagnostic power of icVEP was close to that of GCIPL analysis whether the comparison was based on the qualitative or quantitative data.

Optic Disc and Macular Imaging in Blind Eyes from Non-glaucomatous Optic Neuropathy: A Study with Spectral-domain Optical Coherence Tomography.

The purpose of this study was to determine and compare the optic disc and macular thickness measurements using two spectral-domain optical coherence tomography (SD-OCT) instruments in long-standing blind eyes diagnosed with non-glaucomatous optic neuropathies (NGON). A prospective observational case-series design was used. Twelve eyes from 12 NGON patients with no light perception for at least 6 months underwent optic disc and macular imaging with Cirrus HD-OCT and Spectralis OCT. The correlation between the peripapillary retinal nerve fibre layer (PRNFL) and macular ganglion cell layer and inner plexiform layer (GCL+IPL) thicknesses, and between the duration of no light perception (NLP) and PRNFL/GCL+IPL thicknesses were determined using Spearman's correlation analysis. The mean average PRNFL thickness was 55.9 ± 4.8 µm for Cirrus HD-OCT, which was significantly thicker than that measured by Spectralis OCT (31.9 ± 7.4 µm; p < 0.001). The mean central macular thickness on Cirrus HD-OCT was normal, but there was global thinning at the other macular areas. The mean average GCL+IPL thickness on Cirrus HD-OCT was 51.8 ± 5.8 µm. There was a good correlation between average PRNFL thickness and GCL+IPL thickness (r = 0.830, p = 0.002); however, there was no significant correlation between the duration of NLP to the average PRNFL thickness (on either instruments) or GCL+IPL thickness on Cirrus HD-OCT (p > 0.7). These results show that there was residual PRNFL thickness in NGON eyes with NLP, which varied significantly between SD-OCT instruments. The values of the residual PRNFL and GCL+IPL thicknesses in blind eyes (the "floor" effect) may be useful for prognostic purposes for patients with partial optic atrophy.

Quantitative comparison of disc rim color in optic nerve atrophy of compressive optic neuropathy and glaucomatous optic neuropathy.

PURPOSE: The purpose was to investigate an objective and quantitative method to estimate the redness of the optic disc neuroretinal rim, and to determine the usefulness of this method to differentiate compressive optic neuropathy (CON) from glaucomatous optic neuropathy (GON). METHODS: In our study there were 126 eyes: 40 with CON, 40 with normal tension glaucoma (NTG), and 46 normal eyes (NOR). Digital color fundus photographs were assessed for the redness of disc rim color using ImageJ software. We separately measured the intensity of red, green, and blue pixels from RGB images. Three disc color indices (DCIs), which indicate the redness intensity, were calculated through existing formulas. RESULTS: All three DCIs of CON were significantly smaller than those of NOR (P < 0.001). In addition, when compared with NTG, DCIs were also significantly smaller in CON (P < 0.05). A comparison of mild CON and mild NTG (mean deviation (MD) > -6 dB), in which the extent of retinal nerve fiber layer thinning is comparable, the DCIs of mild CON were significantly smaller than those of mild NTG (P < 0.05). In contrast, DCIs did not differ between moderate-to-severe stages of CON and NTG (MD ≤ -6 dB), though the retinal nerve fibers of CON were more severely damaged than those of NTG. To differentiate between mild CON and mild NTG, all AUROCs for the three DCIs were above 0.700. CONCLUSIONS: A quantitative and objective assessment of optic disc color was useful in differentiating early-stage CON from GON and NOR.

[Optical coherence tomography angiography in glaucoma diagnosis]. / Opticheskaia kogerentnaia tomografiia s funktsiei angiografii v diagnostike glaukomy.

According to literature data, vascular dysfunction may well contribute to the development of glaucomatous optic neuropathy, which makes it reasonable to search for new imaging techniques capable of early diagnosis and monitoring of glaucoma through assessment of retinal, optic nerve head (ONH), and choroidal perfusion. Optical coherence tomography angiography (OCTA), a recently introduced method based on the split-spectrum amplitude-decorrelation angiography (SSADA) algorithm, enables evaluation of both retinal and choroidal blood flow in peripapillary and macular areas. The first studies involving OCTA have revealed a decrease in retinal blood flow in glaucoma. It has also been shown that visual field indices correlate better with the peripapillary flow index than with morphometric parameters of the optic nerve head (ONH) and peripapillary retina. OCT angiography has great potential for ONH blood flow assessment during physiological tests, which is an important step towards understanding pathogenesis of glaucoma.

Assessment of retinal ganglion cell damage in glaucomatous optic neuropathy: Axon transport, injury and soma loss.

Glaucoma is a disease characterized by progressive axonal pathology and death of retinal ganglion cells (RGCs), which causes structural changes in the optic nerve head and irreversible vision loss. Several experimental models of glaucomatous optic neuropathy (GON) have been developed, primarily in non-human primates and, more recently and commonly, in rodents. These models provide important research tools to study the mechanisms underlying glaucomatous damage. Moreover, experimental GON provides the ability to quantify and monitor risk factors leading to RGC loss such as the level of intraocular pressure, axonal health and the RGC population. Using these experimental models we are able to gain a better understanding of GON, which allows for the development of potential neuroprotective strategies. Here we review the advantages and disadvantages of the relevant and most often utilized methods for evaluating axonal degeneration and RGC loss in GON. Axonal pathology in GON includes functional disruption of axonal transport (AT) and structural degeneration. Horseradish peroxidase (HRP), rhodamine-B-isothiocyanate (RITC) and cholera toxin-B (CTB) fluorescent conjugates have proven to be effective reporters of AT. Also, immunohistochemistry (IHC) for endogenous AT-associated proteins is often used as an indicator of AT function. Similarly, structural degeneration of axons in GON can be investigated via changes in the activity and expression of key axonal enzymes and structural proteins. Assessment of axonal degeneration can be measured by direct quantification of axons, qualitative grading, or a combination of both methods. RGC loss is the most frequently quantified variable in studies of experimental GON. Retrograde tracers can be used to quantify RGC populations in rodents via application to the superior colliculus (SC). In addition, in situ IHC for RGC-specific proteins is a common method of RGC quantification used in many studies. Recently, transgenic mouse models that express fluorescent proteins under the Thy-1 promoter have been examined for their potential to provide specific and selective labeling of RGCs for the study of GON. While these methods represent important advances in assessing the structural and functional integrity of RGCs, each has its advantages and disadvantages; together they provide an extensive toolbox for the study of GON.

Enhanced Depth Imaging of Central Laminar Thickness in Optic Neuropathy: Comparison with Normal Eyes.

The purpose of this study was to compare central laminar thickness (LT) among patients with glaucomatous optic neuropathy (GON), patients with non-GON, and normal subjects using enhanced-depth imaging optical coherence tomography (EDI-OCT). Enrolled were 57 patients (n = 64 eyes), including 30 women and 27 men. Three groups were identified: GON (n = 18 eyes), non-GON (n = 16 eyes), and control (n = 30 eyes). The GON group comprised eyes with primary open-angle glaucoma (POAG) (n = 9) and normal-tension glaucoma (NTG) (n = 9). The non-GON group comprised eyes with demyelinating optic neuritis (n = 9), anterior ischemic optic neuropathy (AION) (n = 2), compressive ON (n = 2), Leber hereditary ON (n = 2), and traumatic ON (n = 1). GON and non-GON groups were further divided into mild, moderate, and severe subgroups. Inclusion in the GON group was based on mean deviations (MDs) of visual fields; inclusion in the non-GON group was based on critical flicker frequency (CFF) responses. Intraclass correlation coefficients (ICCs) were used to verify reproducibility of measurements. LTs of GON and non-GON group eyes were thinner than those of control group eyes (p < 0.01); LTs of GON group eyes were thinner than those of non-GON group eyes (p = 0.01). LTs of severe GON subgroup eyes were thinner than those of moderate and mild GON subgroup eyes (p < 0.001; p = 0.024, respectively). LTs of severe non-GON subgroup eyes were thinner than those of mild non-GON subgroup eyes (p = 0.002). These results show that EDI-OCT is valuable for documenting structural abnormalities in optic neuropathy (ON).

Role of nitric oxide in optic nerve head blood flow regulation during an experimental increase in intraocular pressure in healthy humans.

The present study set out to investigate whether nitric oxide, a potent vasodilator, is involved in the regulatory processes in optic nerve head blood flow during an experimental increase in intraocular pressure (IOP). The study was conducted in a randomized, double-masked, placebo-controlled, three way cross-over design. 12 healthy subjects were scheduled to receive either L-NMMA (an unspecific nitric oxide synthase inhibitor), phenylephrine (an α-adrenoceptor agonist) or placebo on three different study days. Optic nerve head blood flow was measured using laser Doppler flowmetry and IOP was increased stepwise with a suction cup. Mean arterial pressure (MAP) and IOP were measured non-invasively and ocular perfusion pressure (OPP) was calculated as OPP = 2/3 MAP-IOP. Administration of L-NMMA and phenylephrine significantly increased MAP and therefore OPP at rest (p < 0.01). L-NMMA significantly reduced baseline blood flow in the optic nerve head (p < 0.01). Application of the suction cup induced a significant increase in IOP and a decrease in OPP (p < 0.01). During the stepwise increase in IOP, some autoregulatory potential was observed until OPP decreased approximately -30% below baseline. None of the administered substances had an effect on this autoregulatory behavior (p = 0.49). The results of the present study confirm that the human optic nerve head shows some regulatory capacity during a decrease in OPP. Nitric oxide is involved in the regulation of basal vascular tone in the optic nerve head but does not seem to be involved in the regulatory mechanisms during an acute increase in IOP in young healthy subjects.

The Definition of Glaucomatous Optic Neuropathy in Artificial Intelligence Research and Clinical Applications.

OBJECTIVE: Although artificial intelligence (AI) models may offer innovative and powerful ways to use the wealth of data generated by diagnostic tools, there are important challenges related to their development and validation. Most notable is the lack of a perfect reference standard for glaucomatous optic neuropathy (GON). Because AI models are trained to predict presence of glaucoma or its progression, they generally rely on a reference standard that is used to train the model and assess its validity. If an improper reference standard is used, the model may be trained to detect or predict something that has little or no clinical value. This article summarizes the issues and discussions related to the definition of GON in AI applications as presented by the Glaucoma Workgroup from the Collaborative Community for Ophthalmic Imaging (CCOI) US Food and Drug Administration Virtual Workshop, on September 3 and 4, 2020, and on January 28, 2022. DESIGN: Review and conference proceedings. SUBJECTS: No human or animal subjects or data therefrom were used in the production of this article. METHODS: A summary of the Workshop was produced with input and approval from all participants. MAIN OUTCOME MEASURES: Consensus position of the CCOI Workgroup on the challenges in defining GON and possible solutions. RESULTS: The Workshop reviewed existing challenges that arise from the use of subjective definitions of GON and highlighted the need for a more objective approach to characterize GON that could facilitate replication and comparability of AI studies and allow for better clinical validation of proposed AI tools. Different tests and combination of parameters for defining a reference standard for GON have been proposed. Different reference standards may need to be considered depending on the scenario in which the AI models are going to be applied, such as community-based or opportunistic screening versus detection or monitoring of glaucoma in tertiary care. CONCLUSIONS: The development and validation of new AI-based diagnostic tests should be based on rigorous methodology with clear determination of how the reference standards for glaucomatous damage are constructed and the settings where the tests are going to be applied. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Intravitreal Neuroglobin Mitigates Primate Experimental Glaucomatous Structural Damage in Association with Reduced Optic Nerve Microglial and Complement 3-Astrocyte Activation.

Current management of glaucomatous optic neuropathy is limited to intraocular pressure control. Neuroglobin (Ngb) is an endogenous neuroprotectant expressed in neurons and astrocytes. We recently showed that exogenous intravitreal Ngb reduced inflammatory cytokines and microglial activation in a rodent model of hypoxia. We thus hypothesised that IVT-Ngb may also be neuroprotective in experimental glaucoma (EG) by mitigating optic nerve (ON) astrogliosis and microgliosis as well as structural damage. In this study using a microbead-induced model of EG in six Cynomolgus primates, optical coherence imaging showed that Ngb-treated EG eyes had significantly less thinning of the peripapillary minimum rim width, retinal nerve fibre layer thickness, and ON head cupping than untreated EG eyes. Immunohistochemistry confirmed that ON astrocytes overexpressed Ngb following Ngb treatment. A reduction in complement 3 and cleaved-caspase 3 activated microglia and astrocytes was also noted. Our findings in higher-order primates recapitulate the effects of neuroprotection by Ngb treatment in rodent EG studies and suggest that Ngb may be a potential candidate for glaucoma neuroprotection in humans.