Artificial intelligence in individualized retinal disease management

Owing to the rapid development of modern computer technologies,artificial intelligence(AI)has emerged as an essential instrument for intelligent analysis across a range of fields.AI has been proven to be highly effective in ophthalmology,where it is frequently used for identifying,diagnosing,and typing retinal diseases.An increasing number of researchers have begun to comprehensively map patients’retinal diseases using AI,which has made individualized clinical prediction and treatment possible.These include prognostic improvement,risk prediction,progression assessment,and interventional therapies for retinal diseases.Researchers have used a range of input data methods to increase the accuracy and dependability of the results,including the use of tabular,textual,or image-based input data.They also combined the analyses of multiple types of input data.To give ophthalmologists access to precise,individualized,and high-quality treatment strategies that will further optimize treatment outcomes,this review summarizes the latest findings in AI research related to the prediction and guidance of clinical diagnosis and treatment of retinal diseases.

Retinal nerve fiber layer defects and chronic kidney disease:the Kailuan Eye Study

AIM:To investigate whether retinal nerve fiber layer defects(RNFLDs)is a potential risk factor for chronic kidney disease(CKD)in Chinese adults.METHODS:The Kailuan Eye Study was a populationbased study that included 14440 participants.All participants underwent detailed assessments,RNFLDs were diagnosed using color fundus photographs.RESULTS:Overall,12507 participants[8533 males(68.23%)]had complete systemic examination data and at least one evaluable fundus photograph.RNFLDs were found in 621 participants[5.0%;95%confidence interval(CI):4.6%-5.34%],and 70 cases of multiple RNFLDs were found(11.27%).After adjusting multiple factors,RNFLDs was significantly associated with CKD severity,the ORs of CKD stage 3,stage 4 and stage 5 were 1.698,4.167,and 9.512,respectively.Multiple RNFLDs were also associated with CKD severity after adjusting multiple factors,the ORs of CKD stage 3 and stage 5 were 4.465 and 11.833 respectively.Furthermore,2294 participants had CKD(18.34%,95%CI:17.68%-18.99%).After adjusting for other factors,CKD presence was significantly correlated with the presence of RNFLDs.CONCLUSION:The strongest risk factors for RNFLDs are CKD and hypertension.Conversely,RNFLDs can be an ocular feature in patients with CKD.Fundoscopy can help detect systemic diseases,and assessment for RNFLDs should be considered in CKD patients.

Retinal capillary plexus in Parkinson’s disease using optical coherence tomography angiography

AIM:To evaluate the alterations of the retinal microvasculature and foveal avascular zone in patients with Parkinson’s disease(PD)using optical coherence tomography angiography(OCT-A).METHODS:A retrospective study of PD patients examined in the Ophthalmology Department of the General Hospital of Athens,“Georgios Gennimatas”from March 2021 to March 2022 was conducted.Totally 44 patients with PD were included and 18 healthy controls were examined,hence a total of 124 eyes were enrolled in the study.The foveal and parafoveal superficial and deep capillary plexus vascular density(fSCP-VD,fDCP-VD,pSCP-VD,pDCP-CD)and foveal avascular zone(FAZ)were quantified with OCTA.Optical coherence tomography(OCT)was used to measure macular thickness.Our statistical analysis was conducted by using a mixed effect linear regression model.RESULTS:After adjustment for age and gender,the mean parafoveal superficial capillary plexus vascular density(pSCP-VD)and mean parafoveal deep capillary plexus vascular density(pDCP-VD)were significantly decreased in individuals with PD(P<0.001 in both)by-2.35(95%CI-3.3,-1.45)and-7.5(95%CI-10.4,-4.6)respectively.fSCP-VD and fDCP-VD didn’t approach statistical significance.The FAZ area and perimeter were significantly decreased(P<0.001 in both)by-0.1 mm^(2)(95%CI-0.13,-0.07)and-0.49 mm^(2)(95%CI-0.66,-0.32)respectively.Circularity didn’t approach statistical significance.Central retinal thickness(CRT)was significantly decreased in individuals with PD(P<0.001)by-23.1μm(95%CI-30.2,-16)and temporal retinal thickness(TRT)was decreased(P=0.025)by-11μm(95%CI-22,-1.5)while nasal retinal thickness(NRT)only approached statistical significance(P=0.066).CONCLUSION:The mean pSCP-VD,pDCP-VD,CRT and TRT are significantly decreased and FAZ is altered in individuals with PD.These findings can be potentially used as biomarkers for the diagnosis and evaluation of early PD.

Therapeutic effect of microencapsulated porcine retinal pigmented epithelial cells transplantation on rat model of Parkinson's disease

Object To investigate the therapeutic effect of microencapsulated porcine retinal pigmented epithelial cells （RPE-M） transplantation on rat model of Parkinson＇s disease （PD）. Methods Primary porcine RPE cells were harvested by enzyme digestion and expanded in culture medium. Determine the levels ofdopamine （DA） and homovanillic acid （HVA） by high performance liquid chromatography electrochemical （HPLC） assay, and the levels of brain-derived neurotrophic factor （BDNF） and glial-derived neurotrophic factor （GDNF） were detected by ELISA. Alginate-polylysine-alginate （APA） microencapsulated cells were produced by using a high voltage electrostatic system. PD rat model was established by unilateral injection of 6-hydroxydopamine （6-OHDA） into the medial forebrain bundle （MFB）. After that, the RPE-M was transplanted into the corpus striatum of PD rat, and then the rotation test scores were recorded and biochemical changes of the corpus striatum were tested. Results The levels of DA, HVA, BDNF and GDNF secreted by RPE were stable in the RPE culture supernatant and were not changed by the microencapsulation. Eighty-three percent rats developed PD by unilateral lesion of 6-OHDA in the MFB. The RPE-M transplantation had therapeutic effect on 33% PD rats. Conclusion Porcine RPE cells grow actively in vitro and could secrete DA, HVA, BDNF, and GDNF constantly, which does not be affected by the passage culture and the APA miroencapsulation. RPE-M transplantation of may be a curative therapy for PD.

Pyrroloquinoline quinone:a potential neuroprotective compound for neurodegenerative diseases targeting metabolism

Pyrroloquinoline quinone is a quinone described as a cofactor for many bacterial dehydrogenases and is reported to exert an effect on metabolism in mammalian cells/tissues.Pyrroloquinoline quinone is present in the diet being available in foodstuffs,conferring the potential of this compound to be supplemented by dietary administration.Pyrroloquinoline quinone’s nutritional role in mammalian health is supported by the extensive deficits in reproduction,growth,and immunity resulting from the dietary absence of pyrroloquinoline quinone,and as such,pyrroloquinoline quinone has been considered as a“new vitamin.”Although the classification of pyrroloquinoline quinone as a vitamin needs to be properly established,the wide range of benefits for health provided has been reported in many studies.In this respect,pyrroloquinoline quinone seems to be particularly involved in regulating cell signaling pathways that promote metabolic and mitochondrial processes in many experimental contexts,thus dictating the rationale to consider pyrroloquinoline quinone as a vital compound for mammalian life.Through the regulation of different metabolic mechanisms,pyrroloquinoline quinone may improve clinical deficits where dysfunctional metabolism and mitochondrial activity contribute to induce cell damage and death.Pyrroloquinoline quinone has been demonstrated to have neuroprotective properties in different experimental models of neurodegeneration,although the link between pyrroloquinoline quinone-promoted metabolism and improved neuronal viability in some of such contexts is still to be fully elucidated.Here,we review the general properties of pyrroloquinoline quinone and its capacity to modulate metabolic and mitochondrial mechanisms in physiological contexts.In addition,we analyze the neuroprotective properties of pyrroloquinoline quinone in different neurodegenerative conditions and consider future perspectives for pyrroloquinoline quinone’s potential in health and disease.

Sickle cell retinopathy and systemic disease

Sickle cell disease(SCD)is a widespread hemoglobinopathy that results in significant patient morbidity and mortality.Vascular occlusion can cause acute pain,acute chest syndrome,and avascular necrosis,while hemolysis and endothelial disruption can cause ischemic stroke,leg ulcers,pulmonary hypertension,and priapism.All ocular and orbital structures can be affected by SCD ischemic events,including orbital bone infarction,ischemic optic neuropathy,retinal artery occlusion,hyphema,secondary glaucoma,sickle cell maculopathy,and sickle cell retinopathy.Proliferative sickle cell retinopathy(PSR)is the most common cause of vision loss.Untreated PSR can lead to macular ischemia,vitreous hemorrhage,and tractional retinal detachment.Ophthalmic screening exams and multimodal imaging can lead to earlier detection of sickle cell retinopathy and improved patient outcomes.SCD patients undergoing vitreoretinal surgery may require coordination of care with hematologists to avoid ischemic complications.While hydroxyurea was the only United States Food and Drug Administration approved treatment for several decades,patients with SCD now have several more treatment options.Despite the United States screening all infants for SCD,there can be delays in diagnosis and treatment.This review article aims to provide an overview of sickle disease for the ophthalmologist,and to discuss emerging treatment options and current management of SCD ocular complications.

Mesenchymal stem cell therapy in retinal and optic nerve diseases: An update of clinical trials

Retinal and optic nerve diseases are degenerative ocular pathologies which lead to irreversible visual loss. Since the advanced therapies availability, cell-based therapies offer a new all-encompassing approach. Advances in the knowledge of neuroprotection, immunomodulation and regenerative properties of mesenchymal stem cells(MSCs) have been obtained by several preclinical studies of various neurodegenerative diseases. It has provided the opportunity to perform the translation of this knowledge to prospective treatment approaches for clinical practice. Since 2008, several first steps projecting new treatment approaches, have been taken regarding the use of cell therapy in patients with neurodegenerative pathologies of optic nerve and retina. Most of the clinical trials using MSCs are in Ⅰ/Ⅱ phase, recruiting patients or ongoing, and they have as main objective the safety assessment of MSCs using various routes of administration. However, it is important to recognize that, there is still a long way to go to reach clinical trials phase Ⅲ-Ⅳ. Hence, it is necessary to continue preclinical and clinical studies to improve this new therapeutic tool. This paper reviews the latest progress of MSCs in human clinical trials for retinal and optic nerve diseases.

The role of Toll-like receptors in retinal ischemic diseases

Toll-like receptors（TLRs） are commonly referred to a series of evolutionary conserved receptors which recognize and respond to various microbes and endogenous ligands.Growing evidence has demonstrated that the expression of TLRs in the retina is regulated during retinal ischemic diseases,including ischemia-reperfusion injury,glaucoma,diabetic retinopathy（DR） and retinopathy of prematurity（ROP）.TLRs can be expressed in multiple cells in the retina,such as glial cells,retinal pigment epithelium（RPE）,as well as photoreceptor cells and endothelium cells.Activation of TLRs in retina could initiate a complex signal transduction cascade,induce the production of inflammatory cytokines and regulate the level of costimulatory molecules,which play prominent roles in the pathogenesis of retinal ischemic diseases.In this review,we summarized current studies about the relationship between TLRs and ischemic retinopathy.A greater understanding of the effect of TLRs on ischemic injuries may contribute to the development of specific TLR targeted therapeutic strategies in these conditions.

Beneficial effects of saffron(Crocus sativus L.) in ocular pathologies, particularly neurodegenerative retinal diseases

Saffron(Crocus sativus L.)has been traditionally used in food preparation and as a medicinal plant.It currently has numerous therapeutic properties attributed to it,such as protection against ischemia,as well as anticonvulsant,antidepressant,anxiolytic,hypolipidemic,anti-atherogenic,anti-hypertensive,antidiabetic,and anti-cancer properties.In addition,saffron has remarkable beneficial properties,such as anti-apoptotic,anti-inflammatory and antioxidant activities,due to its main metabolites,among which crocin and crocetin stand out.Furthermore,increasing evidence underwrites the possible neuroprotective role of the main bioactive saffron constituents in neurodegenerative diseases,such as Parkinson’s and Alzheimer’s diseases,both in experimental models and in clinical studies in patients.Currently,saffron supplementation is being tested for ocular neurodegenerative pathologies,such as diabetic retinopathy,retinitis pigmentosa,age-related macular degeneration and glaucoma,among others,and shows beneficial effects.The present article provides a comprehensive and up to date report of the investigations on the beneficial effects of saffron extracts on the main neurodegenerative ocular pathologies and other ocular diseases.This review showed that saffron extracts could be considered promising therapeutic agents to help in the treatment of ocular neurodegenerative diseases.

Stem cell therapy in retinal diseases

Alteration of the outer retina leads to various diseases such as age-related macular degeneration or retinitis pigmentosa characterized by decreased visual acuity and ultimately blindness.Despite intensive research in the field of retinal disorders,there is currently no curative treatment.Several therapeutic approaches such as cell-based replacement and gene therapies are currently in development.In the context of cell-based therapies,different cell sources such as embryonic stem cells,induced pluripotent stem cells,or multipotent stem cells can be used for transplantation.In the vast majority of human clinical trials,retinal pigment epithelial cells and photoreceptors are the cell types considered for replacement cell therapies.In this review,we summarize the progress made in stem cell therapies ranging from the pre-clinical studies to clinical trials for retinal disease.

Intravitreal stem cell paracrine properties as a potential neuroprotective therapy for retinal photoreceptor neurodegenerative diseases

Retinal degenerations are the leading causes of irreversible visual loss worldwide. Many pathologies included under this umbrella involve progressive degeneration and ultimate loss of the photoreceptor cells, with age-related macular degeneration and inherited and ischemic retinal diseases the most relevant. These diseases greatly impact patients' daily lives, with accompanying marked social and economic consequences. However, the currently available treatments only delay the onset or slow progression of visual impairment, and there are no cures for these photoreceptor diseases. Therefore, new therapeutic strategies are being investigated, such as gene therapy, optogenetics, cell replacement, or cell-based neuroprotection. Specifically, stem cells can secrete neurotrophic, immunomodulatory, and anti-angiogenic factors that potentially protect and preserve retinal cells from neurodegeneration. Further, neuroprotection can be used in different types of retinal degenerative diseases and at different disease stages, unlike other potential therapies. This review summarizes stem cell-based paracrine neuroprotective strategies for photoreceptor degeneration, which are under study in clinical trials, and the latest preclinical studies. Effective retinal neuroprotection could be the next frontier in photoreceptor diseases, and the development of novel neuroprotective strategies will address the unmet therapeutic needs.

Optical coherence tomography assessed retinal nerve fiber layer thickness in patients with Alzheimer's disease:a meta-analysis

AIM:To investigate the difference of retinal nerve fiber layer(RNFL) thickness between Alzheimer's disease patients and normal people,so as to provide clue for the early diagnosis of Alzheimer's disease.· METHODS:The articles on the association of RNFL thickness and Alzheimer's disease were retrieved by searching international and national databases.The qualified articles were assessed by meta analysis with Stata11.0 software.The results were pooled using weighted mean difference(WMD) with a corresponding 95% confidence interval(CI).· RESULTS:Totally 7 studies enrolled 324 eyes were included in the meta-analysis.The results of meta analysis showed that in AD patients,there was a significant average RNFL thickness reduction compared with the control group [WMD=-17.561,95%CI:(-23.971,-11.151)].There were significant differences in superior,inferior,nasal and temporal RNFL thickness between the two groups.WMD with a 95%CI were [-18.829,95%CI:(-25.915,-11.743);P<0.05],[-25.775,95%CI:(-34.304,-17.247);P <0.05],[-16.877,95%CI:(-29.141,-4.613);P<0.001] and [-14.565,95%CI:(-28.002,-1.128);P<0.001] respectively.Begg's test and Egger's test did not show significant difference,funnel plot was basically symmetrical,indicating that there was no publication bias existed.· CONCLUSION:There are significant differences in the RNFL thickness in all quadrants between the two groups.RNFL thickness is reduced in AD patients compared with the control group.·

Novel transscleral sutureless subretinal fluid drainage using a 25-gauge trocar-cannula with a self-closing valve in patients with advanced Coats disease

AIM: To assess surgical outcomes of a novel method of transscleral drainage of subretinal fluid using a 25-gauge trocar-cannula with a self-closing valve(DTV) in patients with severe exudative retinal detachment(ERD) in Coats disease.METHODS: Retrospective consecutive cases of 20 patients(20 eyes) of severe ERD due to Coats disease(stage 3 B) in total 156 Coats patients between June 2015 and April 2019 were included in this study. The participants were aged 1 to 10 y with a mean age of 3.50±1.79 y. The mean follow-up time were 11.9 mo. Subretinal fluid was drained transsclerally using a novel method of DTV. The height of the retinal detachment and the regression of abnormal vessels including telangiectasias and aneurysms were observed. Complications including vitreoretinal fibrosis, tractional retinal detachments(TRD), endophthalmitis, retinal holes, and hemorrhages were evaluated.RESULTS: Following surgeries, the patients showed the replacement of ERD and regression of telangiectatic retinal vessels observed with binocular indirect ophthalmoscopy. Six patients received retinal cryotherapies and 12 patients received laser photocoagulations following first external subretinal fluid drainage using DTV. All patients underwent intravitreal anti-vascular endothelial growth factor therapies to induce residual subretinal fluid absorption. During followups, 8 patients underwent a second drainage operation, 17 patients received retinal laser photocoagulations and 7 patients received cryotherapies. Vitreoretinal fibrosis was found in 7 patients and 6 patients underwent microinvasive vitrectomies during the follow-up period. Severe TRD, iatrogenic retinal holes, and hemorrhages were not found.CONCLUSION: The authors present a new therapeutic approach that successfully drains subretinal fluid in advanced stage 3 B Coats disease with severe ERD. This is a simple, safe and less invasive approach when compared with traditional managements. However, it should be strictly selected for patients with high bullous ERD close to the central axis of the eye in order to avoid the complication of retinal holes.

The role of miRNA in retinal ganglion cell health and disease

miRNA are short non-coding RNA responsible for the knockdown of proteins through their targeting and silencing of complimentary m RNA sequences.The mi RNA landscape of a cell thus affects the levels of its proteins and has significant consequences to its health.Deviations in this mi RNA landscape have been implicated in a variety of neurodegenerative diseases and have also garnered interest as targets for treatment.Retinal ganglion cells are the sole projection neuron of the retina with their axons making up the optic nerve.They are a focus of study not only for their importance in vision and the myriad of blinding diseases characterized by their dysfunction and loss,but also as a model of other central nervous system diseases such as spinal cord injury and traumatic brain injury.This review summarizes current knowledge on the role of mi RNA in retinal ganglion cell function,highlighting how perturbations can result in disease,and how modulating their abundance may provide a novel avenue of therapeutic research.

Mixed Connective Tissue Disease Complicated by Retinal Microvasculopathy and Its Relationship with Fragile-X Syndrome

Purpose: To report an unusual case of retinal microvasculopathy secondary to mixed connective tissue disease (MCTD) on a background history of fragile-X syndrome (FXS). Methods: Case report and literature review. Results: A cotton wool spot was discovered in a 29-year-old female who presented with an ischaemic digit secondary to Raynaud’s phenomenon. She also has a background history of MCTD and FXS. Fundus examination and automated perimetry findings were normal. Magnet resonance imaging and computed tomography aortogram did not demonstrate any evidence of vasculitis in the head and neck. She was tested positively for U1-ribonuclear peptide. Interestingly, the re-distribution of Fragile-X related gene 1 has been suggested to trigger autoimmune responses in experiments. This finding makes the case peculiar as it suggests an alternate explanation for this patient’s clinical findings. Conclusion: Retinal vasculopathy is a rare complication of MCTD. The background history of FXS potentially highlights an alternate autoimmune pathogenetic mechanism.

Automated Classification of Inherited Retinal Diseases in Optical Coherence Tomography Images Using Few-shot Learning

Objective To develop a few-shot learning(FSL) approach for classifying optical coherence tomography(OCT) images in patients with inherited retinal disorders(IRDs).Methods In this study, an FSL model based on a student–teacher learning framework was designed to classify images. 2,317 images from 189 participants were included. Of these, 1,126 images revealed IRDs, 533 were normal samples, and 658 were control samples.Results The FSL model achieved a total accuracy of 0.974–0.983, total sensitivity of 0.934–0.957, total specificity of 0.984–0.990, and total F1 score of 0.935–0.957, which were superior to the total accuracy of the baseline model of 0.943–0.954, total sensitivity of 0.866–0.886, total specificity of 0.962–0.971,and total F1 score of 0.859–0.885. The performance of most subclassifications also exhibited advantages. Moreover, the FSL model had a higher area under curves(AUC) of the receiver operating characteristic(ROC) curves in most subclassifications.Conclusion This study demonstrates the effective use of the FSL model for the classification of OCT images from patients with IRDs, normal, and control participants with a smaller volume of data. The general principle and similar network architectures can also be applied to other retinal diseases with a low prevalence.

Accuracy improvement for classifying retinal OCT images by diseases using deep learning-based selective denoising approach

In ophthalmology,retinal optical coherence tomography(OCT)images with noticeable structural features help identify human eyes as healthy or diseased.The recently hot arti ficial intelligence(AI)realized this recognition process automatically.However,speckle noise in the original retinal OCT image reduces the accuracy of disease classi fication.This study presents a timesaving approach based on deep learning to improve classi fication accuracy by removing the noise from the original dataset.Firstly,four pre-trained convolutional neural networks(CNNs)from the ImageNet Large Scale Visual Recognition Challenge(ILSVRC)were trained to classify the original images into two categories:The noise reduction required(NRR)and the noise-free(NF)images.Among the CNNs,VGG19 BN performed best with 98%accuracy and 99%recall.Then,we used the block-matching and 3D filtering(BM3D)algorithm to denoise the NRR images.Those noise-removed NRR and the NF images form the processed dataset.The quality of images in the dataset is prominently ameliorated after denoising,which is valid to improve the models'performance.The original and processed datasets were tested on the four pre-trained CNNs to evaluate the effectiveness of our proposed approach.We have compared the CNNs,and the results show the performance of the CNNs trained with the processed dataset is improved by an average of 2.04%,5.19%,and 5.10%under overall accuracy(OA),Macro F1-score,and Micro F1-score,respectively.Especially for DenseNet161,the OA is improved to 98.14%.Our proposed method demonstrates its effectiveness in improving classi fication accuracy and opens a new solution to reduce denoising time-consuming for large datasets.

Varicose Veins, Retinal Tears and Deep Vein Thrombosis, New Insights into the Causes from Adams Disease

Adams disease is the consequence of overly active transient receptor potential cation channels (TRP). This case report presents a patient suffering from multiple vascular problems and may provide new insights into the causes of venous problems. Endothelial and smooth muscle cells in veins contain TRP. These channels when activated excessively result in calcium accumulation, oxygen radical formation and apoptosis of endothelial and smooth muscle cells. The death of critical cells in vein valves, may lead to varicose veins. The loss of endothelial cells in venules may lead to retinal tears. Damage to vein walls may lead to a deep vein thrombosis. Transient receptor potential cation channels may be new drug targets of interest in the treatment or prevention of these conditions.

Game Theory-Based Dynamic Weighted Ensemble for Retinal Disease Classification

An automated retinal disease detection system has long been in exis-tence and it provides a safe,no-contact and cost-effective solution for detecting this disease.This paper presents a game theory-based dynamic weighted ensem-ble of a feature extraction-based machine learning model and a deep transfer learning model for automatic retinal disease detection.The feature extraction-based machine learning model uses Gaussian kernel-based fuzzy rough sets for reduction of features,and XGBoost classifier for the classification.The transfer learning model uses VGG16 or ResNet50 or Inception-ResNet-v2.A novel ensemble classifier based on the game theory approach is proposed for the fusion of the outputs of the transfer learning model and the XGBoost classifier model.The ensemble approach significantly improves the accuracy of retinal disease pre-diction and results in an excellent performance when compared to the individual deep learning and feature-based models.