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Key Points Blindness affects millions of people worldwide. The leading causes of irreversible visual impairment include age-related macular degeneration (AMD), retinal vascular diseases and glaucoma. During the past decade there have been substantial advances in our understanding of the pathogenesis and genetics of ophthalmic diseases, and the extent of treatable conditions and treatment options continues to increase. Intravitreal injection of anti-angiogenic agents has emerged as the most effective therapy for AMD and retinal vascular diseases. Clinical trials are underway to evaluate new drugs directed against several novel targets in the complement system and angiogenic pathways for the treatment of AMD, and neuroprotective drugs are being investigated for the treatment of both AMD and glaucoma. Other promising therapeutics include gene therapy and stem cell therapy. However, there are still no effective therapies for several common disorders that cause blindness, and many individuals with glaucoma develop progressive loss of vision despite receiving treatment with intraocular pressure-lowering drugs. Moreover, intraocular injection is not an ideal drug delivery platform despite the overall efficacy of anti-VEGF (vascular endothelial growth factor) therapies. Present research is aimed at improving our understanding of pathogenic processes, identification of potential therapeutic targets and optimization of ocular drug delivery by utilizing novel strategies such as encapsulated cell technology and applications of nanomedicine. Recent scientific developments have presented new opportunities to make major advances in ophthalmology, and a vigorous effort to develop new therapies is currently underway. During the past decade, there have been substantial advances in our understanding of the pathogenesis and genetics of eye diseases. Focusing on glaucoma and retinal disorders, Zhang and colleagues review the current status of ocular drug therapy, discuss novel agents currently in development and clinical trials and highlight recent advances in drug delivery. Blindness affects 60 million people worldwide. The leading causes of irreversible blindness include age-related macular degeneration, retinal vascular diseases and glaucoma. The unique features of the eye provide both benefits and challenges for drug discovery and delivery. During the past decade, the landscape for ocular drug therapy has substantially changed and our knowledge of the pathogenesis of ophthalmic diseases has grown considerably. Anti-angiogenic drugs have emerged as the most effective form of therapy for age-related macular degeneration and retinal vascular diseases. Lowering intraocular pressure is still the mainstay for glaucoma treatment but neuroprotective drugs represent a promising next-generation therapy. This Review discusses the current state of ocular drug therapy and highlights future therapeutic opportunities.

The ability of deep learning architectures to identify glaucomatous optic neuropathy (GON) in fundus photographs was evaluated. A large database of fundus photographs (n = 14,822) from a racially and ethnically diverse group of individuals (over 33% of African descent) was evaluated by expert reviewers and classified as GON or healthy. Several deep learning architectures and the impact of transfer learning were evaluated. The best performing model achieved an overall area under receiver operating characteristic (AUC) of 0.91 in distinguishing GON eyes from healthy eyes. It also achieved an AUC of 0.97 for identifying GON eyes with moderate-to-severe functional loss and 0.89 for GON eyes with mild functional loss. A sensitivity of 88% at a set 95% specificity was achieved in detecting moderate-to-severe GON. In all cases, transfer improved performance and reduced training time. Model visualizations indicate that these deep learning models relied on, in part, anatomical features in the inferior and superior regions of the optic disc, areas commonly used by clinicians to diagnose GON. The results suggest that deep learning-based assessment of fundus images could be useful in clinical decision support systems and in the automation of large-scale glaucoma detection and screening programs.

The recent advent of continuous intraocular pressure (IOP) telemetry has led to an increased awareness of the importance of IOP fluctuations, and theories have emerged that IOP variations could play as much a role in glaucoma progression as the mean level of IOP. The aim of the present study was to evaluate the direct effect of common daily activities on IOP-related profiles. Primary open-angle glaucoma and glaucoma suspect patients were prospectively enrolled from specialist clinics at the University of California San Diego (UCSD), USA. Patients were fitted with a SENSIMED Triggerfish (TF) contact lens sensor (CLS) and were instructed to return to their usual daily activities for 24 h. They were asked to record each specific activity or event in a diary. The protocol was repeated twice. The following events were recorded: “walking/cycling”, “resistance training”, “yoga/meditation”, and “emotional stress”. CLS measurements recorded 60-to-30 min prior to each event were used as a baseline reference, and all IOP-related fluctuations for 120 min after the start of each event were reported in relation to this reference. Forty relevant events from 22 CLS recordings in 14 patients were retrieved from the diaries. Walking/cycling (n = 10) caused a small but statistically significant elevation of the IOP-related profile during the activity ( p  = 0.018). Resistance training (n = 11) caused a persistent elevation of the IOP-related profile from the onset of the activity ( p  = 0.005) through 120 min after the activity was stopped ( p  = 0.007). Yoga/meditation (n = 4) caused a sustained drop in the IOP-related profiles through to 120 min, although this was not statistically significant ( p  > 0.380). Emotional stress (n = 13) was associated with a gradual elevation of the IOP-related profile from the start of the stressful stimulus. Both early and late variations were statistically significant ( p  = 0.038 and p  = 0.021, respectively). The present study suggests that emotional stress and resistance training may be associated with persistent IOP-related profile elevation.

Acute glaucoma is a sight-threatening condition characterized by a sudden and substantial rise in intraocular pressure (IOP) and consequent retinal ganglion cell (RGC) death. Angle closure glaucoma, a common cause of glaucoma in Asia that affects tens of millions of people worldwide, often presents acutely with loss of vision, pain, and high IOP. Even when medical and surgical treatment is available, acute angle closure glaucoma can cause permanent and irreversible loss of vision. Toll-like receptor 4 (TLR4) signaling has been previously implicated in the pathogenesis of IOP-induced RGC death, although the underlying mechanisms are largely unknown. In the present study, we used an acute IOP elevation/glaucoma model to investigate the underlying mechanism of RGC death. We found that TLR4 leads to increased caspase-8 expression; this elevation increases IL-1β expression and RGC death via a caspase-1–dependent pathway involving Nod-like receptor family, pyrin domain containing 1 (NLRP1)/NLRP3 inflammasomes and a caspase-1–independent pathway. We show that inhibition of caspase-8 activation significantly attenuates RGC death by down-regulating the activation of NLRP1 and NLRP3, thus demonstrating the pivotal role of caspase-8 in the TLR4-mediated activation of inflammasomes. These findings demonstrate collectively a critical role of caspase-8 in transducing TLR4-mediated IL-1β production and RGC death and highlight signal transduction in a caspase-1–dependent NLRP1/NLRP3 inflammasome pathway and a caspase-1–independent pathway in acute glaucoma. These results provide new insight into the pathogenesis of glaucoma and point to a treatment strategy.

To compare the diagnostic abilities of vessel density measurements of the optic nerve head (ONH), peripapillary and macular regions on optical coherence tomography (OCT) angiography in eyes with primary open angle glaucoma (POAG) with that of the ONH rim area, peripapillary retinal nerve fiber layer (RNFL) thickness and the macular ganglion cell complex (GCC) thickness measurements. In a cross sectional study, 78 eyes of 50 control subjects and 117 eyes of 67 POAG patients underwent vessel density and structural measurements with spectral domain OCT. POAG was diagnosed based on the masked evaluation of optic disc stereo photographs. Area under receiver operating characteristic curves (AUC) and sensitivities at fixed specificities of vessel densities in ONH, peripapillary and macular regions were compared with rim area, RNFL and GCC thickness. The AUC (sensitivity at 95% specificity) of average vessel densities within the ONH, peripapillary and macular region were 0.77 (31%), 0.85 (56%) and 0.70 (18%) respectively. The same of ONH rim area, average RNFL and GCC thickness were 0.94 (83%), 0.95 (72%) and 0.93 (62%) respectively. AUCs of vessel densities were significantly lower (p<0.05) than that of the corresponding structural measurements. Pre-treatment IOP (coefficient: 0.08) affected (p<0.05) the AUC of ONH vessel density but not of any other vessel density or structural measurements. Diagnostic abilities of ONH, peripapillary and the macular vessel densities in POAG were significantly lower than ONH rim area, peripapillary RNFL and macular GCC measurements respectively. At fixed levels of glaucoma severity, the diagnostic ability of the ONH vessel density was significantly greater in eyes with higher pre-treatment IOP.

Background/AimsTo evaluate quantitative changes in the foveal avascular zone (FAZ) area after glaucoma surgery using swept-source optical coherence tomography angiography (SS-OCTA).MethodsFifty-four consecutive patients with primary open-angle glaucoma (POAG) who met the inclusion criteria and underwent unilateral glaucoma surgery to reduce intraocular pressure (IOP) between April 2018 and July 2019.Eyes underwent IOP-lowering glaucoma surgery and their fellow (non-surgical) eyes were included. OCTA of the macula was performed in both eyes before glaucoma surgery and 3 months postoperatively. Two blinded examiners reviewed the image quality. Within- and between-group comparisons of the FAZ area and correlation of the FAZ area with age, IOP, central sensitivity and clinical variables.ResultsThe mean (±SD) age was 66.7±11.3 years. After surgery, the IOP and FAZ area significantly decreased from 22.1±9.5 mmHg to 10.3±3.5 mmHg and from 0.485±0.193 mm2 to 0.446±0.174 mm2, respectively (both p<0.001). Conversely, in the non-surgery group, the preoperative and postoperative mean FAZ areas (0.398±0.119 mm2 and 0.396±0.110 mm2, respectively) did not significantly differ (p=0.469). Change in the FAZ area significantly correlated with the preoperative FAZ area, preoperative foveal sensitivity and change in IOP (all p<0.05).ConclusionsThe FAZ area is decreased with IOP-lowering surgery in patients with POAG, and change in the FAZ area was significantly correlated with both preoperative foveal sensitivity and change in IOP.

To evaluate the diagnostic ability of macular ganglion cell and inner plexiform layer measurements in glaucoma, obtained using swept source (SS) and spectral domain (SD) optical coherence tomography (OCT) and to compare to circumpapillary retinal nerve fiber layer (cpRNFL) thickness measurements. The study included 106 glaucomatous eyes of 80 subjects and 41 eyes of 22 healthy subjects from the Diagnostic Innovations in Glaucoma Study. Macular ganglion cell and inner plexiform layer (mGCIPL), macular ganglion cell complex (mGCC) and cpRNFL thickness were assessed using SS-OCT and SD-OCT, and area under the receiver operating characteristic curves (AUCs) were calculated to determine ability to differentiate glaucomatous and healthy eyes and between early glaucomatous and healthy eyes. Mean (± standard deviation) mGCIPL and mGCC thickness were thinner in both healthy and glaucomatous eyes using SS-OCT compared to using SD-OCT. Fixed and proportional biases were detected between SS-OCT and SD-OCT measures. Diagnostic accuracy (AUCs) for differentiating between healthy and glaucomatous eyes for average and sectoral mGCIPL was similar in SS-OCT (0.65 to 0.81) and SD-OCT (0.63 to 0.83). AUCs for average cpRNFL acquired using SS-OCT and SD-OCT tended to be higher (0.83 and 0.85, respectively) than for average mGCC (0.82 and 0.78, respectively), and mGCIPL (0.73 and 0.75, respectively) but these differences did not consistently reach statistical significance. Minimum SD-OCT mGCIPL and mGCC thickness (unavailable in SS-OCT) had the highest AUC (0.86) among macular measurements. Assessment of mGCIPL thickness using SS-OCT or SD-OCT is useful for detecting glaucomatous damage, but measurements are not interchangeable for patient management decisions. Diagnostic accuracies of mGCIPL and mGCC from both SS-OCT and SD-OCT were similar to that of cpRNFL for glaucoma detection.

To measure the parapapillary atrophy (PPA) area in en face images obtained with swept-source optical coherence tomography (SS-OCT), and to evaluate its relationship to glaucoma, myopia, and age in non-highly myopic subjects. Retrospective, cross-sectional study. Fifty eyes of 30 subjects with open-angle glaucoma (G group) and forty-three eyes of 26 healthy control subjects (C group). Eyes with high myopia (spherical equivalent refractive error ≤ -8 diopters or axial length ≥ 26.5 mm) were excluded. Mean age ± standard deviation was 59.9 ± 12.4 years. The beta zone and the gamma zone PPA areas were measured in en face images reconstructed from three-dimensional SS-OCT images. Relationship between the PPA areas and patient characteristics such as glaucoma, axial length, and age was statistically evaluated using multivariate mixed-effects models. Areas of the beta zone and the gamma zone PPA measured on en face OCT images. Average ± standard deviation area of the beta and the gamma zone was 0.64 ± 0.79 and 0.16 ± 0.30 mm2, respectively. In multivariate models, the gamma zone significantly correlated with axial length (P = 0.001) but not with glaucoma (P = 0.944). In contrast, the beta zone significantly correlated with age (P = 0.0249) and glaucoma (P = 0.014). En face images reconstructed from 3D SS-OCT data facilitated measurements of the beta and the gamma PPA zones even in eyes with optic disc distortion. The OCT-defined beta zone is associated with glaucoma and age, whereas the gamma zone correlated with myopia but not with glaucoma. This study confirmed the clinical usefulness of OCT-based classification of the PPA zones in distinguishing glaucomatous damage of the optic nerve from myopic damage in non-highly myopic eyes.

This study compared between TEMPO, a new binocular perimeter, with the Humphrey Field Analyzer (HFA). Patients were tested with both TEMPO 24–2 Ambient Interactive Zippy Estimated by Sequential Testing (AIZE)-Rapid and HFA 24–2 Swedish Interactive Threshold Algorithm (SITA)-Fast in a randomized sequence on the same day. Using a mixed-effects model, visual field (VF) parameters and reliability indices were compared. Retinal nerve fiber layer (RNFL) thickness was measured using Cirrus optical coherence tomography (OCT), and coefficient of determinations for VF and OCT parameters were calculated and compared using Akaike information criteria. 740 eyes (including 68 healthy, 262 glaucoma suspects, and 410 glaucoma) of 370 participants were evaluated. No significant differences were seen in mean deviation and visual field index between the two perimeters (P > 0.05). A stronger association between VF mean sensitivity (dB or 1/L) and circumpapillary RNFL was found for TEMPO (adjusted R 2  = 0.25; Akaike information criteria [AIC] = 5235.5 for dB, and adjusted R 2  = 0.29; AIC = 5200.8 for 1/L, respectively) compared to HFA (adjusted R 2  = 0.22; AIC = 5263.9 for dB, and adjusted R 2  = 0.22; AIC = 5262.7 for 1/L, respectively). Measurement time was faster for TEMPO compared to HFA (261 s vs. 429 s, P < 0.001). Further investigations are needed to assess the long-term monitoring potential of this binocular VF test.

AimsTo compare the intrasession repeatability of peripapillary and macular vessel density measurements of optical coherence tomography angiography (OCTA) in normal and glaucoma eyes, and to evaluate the effect of signal strength of OCTA scans on the repeatability.MethodsIn a cross-sectional study, three optic nerve head scans each of 65 eyes (30 normal, 35 glaucoma eyes) and three macular scans each of 69 eyes (35 normal, 34 glaucoma eyes) acquired in the same session with OCTA were analysed. Repeatability was assessed using within-subject coefficient of repeatability (CRw) and variation (CVw). Effect of signal strength index (SSI) on repeatability was evaluated with repeated-measures mixed-effects models.ResultsCRw (%) and CVw (%) of peripapillary measurements in normal eyes ranged between 3.3 and 7.0, and 2.5 and 4.4 respectively, and that in glaucoma eyes between 3.5 and 7.1, and 2.6 and 6.6. For the macular, these measurements ranged between 4.1 and 6.0, and 3.3 and 4.7 in normal eyes and 4.3 and 6.9, and 3.7 and 5.6 in glaucoma eyes. Repeatability estimates of most measurements were similar in normal and glaucoma eyes. Vessel densities of both peripapillary and macular regions significantly increased with increase in SSI of repeat scans (coefficients ranging from 0.15 to 0.38, p<0.01 for all associations).ConclusionsRepeatability estimates of OCTA measured peripapillary and macular vessel densities were similar in normal eyes and eyes with glaucoma. SSI values of the scans had a significant effect on the repeatability of OCTA with the vessel density values increasing in scans with higher SSI values.