Glaucomatous optic neuropathy treatment options:the promise of novel therapeutics,techniques and tools to help preserve vision

Peripheral vision loss followed by ＂tunnel vision＂ and eventual irreversible blindness is the fate of patients afflicted by various forms of glaucoma including primary open-angle glaucoma（POAG） and normotensive glaucoma（NTG）.These complex and heterogeneous diseases are characterized by extensive death of retinal ganglion cells（RGCs） accompanied by retraction and severance of their axonal connections to the brain and thus damage to and thinning of the optic nerve.Since patients suffering from this glaucomatous optic neuropathy（GON） first notice visual impairment when they have lost 〉 40% of their RGCs,early diagnosis is the key to retard the progression of glaucoma.Elevated intraocular pressure（IOP）,low cerebrospinal and/or low intracranial fluid pressure,advancing age,and ethnicity are major risk factors associated with POAG.However,retinal vascular abnormalities and a high sensitivity of RGCs and optic nerve head components to neurotoxic,inflammatory,oxidative and mechanical insults also contribute to vision loss in POAG/GON.Current treatment modalities for POAG and NTG involve lowering IOP using topical ocular drugs,combination drug products,and surgical interventions.Two recently approved multi-pharmacophoric drugs（e.g.,rho kinase inhibitor,Netarsudil;a drug conjugate,Latanoprostene Bunod） and novel aqueous humor drainage devices（i Stent and Cy Pass） are also gaining acceptance for treating POAG/NTG.Neuroprotective and regenerative agents,coupled with electroceutical,mechanical support systems,stem cell transplantation and gene therapy are emerging therapeutics on the horizon to help combat GON.The latter techniques and approaches hope to rejuvenate RGCs and repair the optic nerve structures,thereby providing a gain of function of the visual system for the glaucoma patients.

Prophylaxis with intraocular pressure lowering medication and glaucomatous progression in patients receiving intravitreal anti-VEGF therapy

AIM: To investigate whether pretreatment with pressurelowering medication prior to anti-vascular endothelial factor(VEGF) injections had an effect on glaucomatous progression in patients with preexisting glaucoma or ocular hypertension(OHT).METHODS: A total of 66 eyes from 54 patients with a preexisting diagnosis of glaucoma or OHT, treated with six or more anti-VEGF injections were selected for chart review. Primary outcome measures were rate of visual field loss in d B/year, rate of change in retinal nerve fiber layer(RNFL) thickness in microns/year, and need for additional glaucoma intervention.RESULTS: The number of eyes requiring additional glaucoma medication was 5 of 20(25.0%) and 14 of 46(30.4%) for the pretreated and non-pretreated groups, respectively. The number of eyes requiring glaucoma laser or surgery was 4 of 20(20.0%) and 13 of 46(28.3%) for the pretreated and non-pretreated groups, respectively. Estimated mean rate of pattern standard deviation decline was not significant in either group(P>0.073), with no difference between groups(P=0.332). Although both groups showed significant RNFL change from baseline(P<0.011), no difference was detected between groups(P=0.467).CONCLUSION: Pretreatment has no detectable effect on structural or functional glaucomatous progression. Patients receiving repeated injections may be at risk for glaucomatous complications requiring invasive intervention.

Fuzzy Difference Equations in Diagnoses of Glaucoma from Retinal Images Using Deep Learning

The intuitive fuzzy set has found important application in decision-making and machine learning.To enrich and utilize the intuitive fuzzy set,this study designed and developed a deep neural network-based glaucoma eye detection using fuzzy difference equations in the domain where the retinal images converge.Retinal image detections are categorized as normal eye recognition,suspected glaucomatous eye recognition,and glaucomatous eye recognition.Fuzzy degrees associated with weighted values are calculated to determine the level of concentration between the fuzzy partition and the retinal images.The proposed model was used to diagnose glaucoma using retinal images and involved utilizing the Convolutional Neural Network(CNN)and deep learning to identify the fuzzy weighted regularization between images.This methodology was used to clarify the input images and make them adequate for the process of glaucoma detection.The objective of this study was to propose a novel approach to the early diagnosis of glaucoma using the Fuzzy Expert System(FES)and Fuzzy differential equation(FDE).The intensities of the different regions in the images and their respective peak levels were determined.Once the peak regions were identified,the recurrence relationships among those peaks were then measured.Image partitioning was done due to varying degrees of similar and dissimilar concentrations in the image.Similar and dissimilar concentration levels and spatial frequency generated a threshold image from the combined fuzzy matrix and FDE.This distinguished between a normal and abnormal eye condition,thus detecting patients with glaucomatous eyes.

Morphological changes in Schlemm's canal in treated and newly diagnosed untreated glaucomatous eyes

A custom built 1310 nm center wavelength swept source optical coherence tomography instrument was used to measure morphological changes in treated and newly diagnosed untreated glaucomatous human Schlemm’s canal(SC).Thirty-seven primary open-angle glaucoma patients were divided into two groups depending on the patients having been treated or not.The statistical results showed that there were significant differences between the treated and untreated groups’SC areas(treated,7935.6875±680.003μm2;untreated,3890.71875±871.49844μm2;P<0.001),the circumferences(treated,580.37891±44.96529μm;untreated,381.9026±41.22123μm;P<0.001),and the long diameters(treated,272.87806±25.7254μm;untreated,185.24047±19.72786μm;P<0.001).We hypothesize that,after drug treatment,the SC will expand and the morphometric values especially the areas will become larger,thus helping to reduce intraocular pressure.

Establishment of an adult zebrafish model of retinal neurodegeneration induced by NMDA

AIM: To establish a model of retinal neurodegeneration induced by N-Methyl-D-aspartic acid(NMDA) in adult zebrafish.METHODS: We compared the effects of three different NMDA delivery methods on retinal neurodegeneration in adult zebrafish: immersion(I.M.), intravitreal injection(I.V.), and intraperitoneal injection(I.P.), and examined retinal pathology and degeneration by hematoxylin and eosin and TUNEL staining in the treated zebrafish. Effects of the NMDA receptor antagonist MK-801 and the natural product resveratrol on NMDA-induced retinal neurodegeneration were also assessed.RESULTS: The thickened inner retina was seen in histology with 100 μmol/L NMDA by I.M. administration. Significant apoptosis in the retinal ganglion cell layer and retinal thickness reduction occurred in 0.5 mol/L NMDA I.P. administration group.Seizure-like behavioral changes, but no retinal histological alteration occurred in 16 mg/kg NMDA I.P. administration group. Resveratrol and MK-801 prevented NMDA-induced retinal neurodegeneration in the zebrafish. CONCLUSION: Among the three drug administration methods, I.V. injection of NMDA is the most suitable for establishment of an acute retinal damage model inzebrafish. I.M. with NMDA is likely the best for use as a chronic retinal damage model. I.P. treatment with NMDA causes brain damage. Resveratrol and MK801 may be a clinically valuable treatment for retinal neurodegeneration.

Automatic counting of retinal ganglion cells in the entire mouse retina based on improved YOLOv5

Glaucoma is characterized by the progressive loss of retinal ganglion cells (RGCs),although the pathogenic mechanism remains largely unknown.To study the mechanism and assess RGC degradation,mouse models are often used to simulate human glaucoma and specific markers are used to label and quantify RGCs.However,manually counting RGCs is time-consuming and prone to distortion due to subjective bias.Furthermore,semi-automated counting methods can produce significant differences due to different parameters,thereby failing objective evaluation.Here,to improve counting accuracy and efficiency,we developed an automated algorithm based on the improved YOLOv5 model,which uses five channels instead of one,with a squeeze-and-excitation block added.The complete number of RGCs in an intact mouse retina was obtained by dividing the retina into small overlapping areas and counting,and then merging the divided areas using a non-maximum suppression algorithm.The automated quantification results showed very strong correlation (mean Pearson correlation coefficient of 0.993) with manual counting.Importantly,the model achieved an average precision of 0.981.Furthermore,the graphics processing unit (GPU) calculation time for each retina was less than 1 min.The developed software has been uploaded online as a free and convenient tool for studies using mouse models of glaucoma,which should help elucidate disease pathogenesis and potential therapeutics.

Finite element analysis of trans-lamina cribrosa pressure difference on optic nerve head biomechanics: the Beijing Intracranial and Intraocular Pressure Study

The present study aims to assess the potential difference of biomechanical response of the optic nerve head to the same level of trans-lamina cribrosa pressure difference(TLCPD) induced by a reduced cerebrospinal fluid pressure(CSFP) or an elevated intraocular pressure(IOP). A finite element model of optic nerve head tissue(pre-and post-laminar neural tissue, lamina cribrosa, sclera, and pia mater) was constructed. Computed stresses, deformations, and strains were compared at each TLCPD step caused by reduced CSFP or elevated IOP. The results showed that elevating TLCPD increased the strain in optic nerve head,with the largest strains occurring in the neural tissue around the sclera ring. Relative to a baseline TLCPD of 10 mmHg, at a same TLCPD of 18 mmHg, the pre-laminar neural tissue experienced 11.10% first principal strain by reduced CSFP and 13.66% by elevated IOP, respectively. The corresponding values for lamina cribrosa were 6.09% and 6.91%. In conclusion, TLCPD has a significant biomechanical impact on optic nerve head tissue and, more prominently, within the pre-laminar neural tissue and lamina cribrosa. Comparatively, reducing CSFP showed smaller strain than elevating IOP even at a same level of TLCPD on ONH tissue, indicating a different potential role of low CSFP in the pathogenesis of glaucoma.