Irreversible Retinal Damage Research Articles

A New Ex Vivo Model Based on Mouse Retinal Explants for the Study of Ocular Toxoplasmosis.

Ocular toxoplasmosis is the most prevalent clinical manifestation of T. gondii infection, which causes irreversible retinal damage. Different experimental models have been developed to study this pathology. In the present study, a new, ex vivo model is proposed to contribute to the elucidation of disease mechanisms and to possible therapeutic solutions. Ex-vivo retinal explants, prepared from mouse retinas following established protocols, were incubated with T. gondii tachyzoites maintained in Vero cells. At different times, starting at 12 h up to 10 days of incubation, the explants were analyzed with immunofluorescence and Western blot to investigate their responses to parasite infection. T. gondii invasion of the retinal thickness was evident after 3 days in culture, where parasites could be detected around retinal cell nuclei. This was paralleled by putative cyst formation and microglial activation. At the same time, an evident increase in inflammatory and oxidative stress markers was detected in infected explants compared to controls. Cell death also appeared to occur in retinal explants after 3 days of T. gondii infection, and it was characterized by increased necroptotic but not apoptotic markers. The proposed model recapitulates the main characteristics of T. gondii retinal infection within 3 days of incubation and, therefore, allows for studying the very early events of the process. In addition, it requires only a limited number of animals and offers easy manipulation and accessibility for setting up different experimental conditions and assessing the effects of putative drugs for therapy.

Naked-Eye 3-Dimensional Vision Training for Myopia Control

Early onset of myopia increases the risk of high myopia, which can lead to irreversible retinal damage and even loss of central vision. To investigate the efficacy and safety of naked-eye 3-dimensional vision training (NVT) in preventing the progression of myopia in children. This randomized clinical trial was conducted in 3 hospitals from May 25, 2022, to February 24, 2023. Participants were children (aged 6-18 years) who had a diagnosis of myopia with a spherical equivalent refraction of -0.75 to -6.00 diopters (D). Children in the intervention group received 20 minutes of NVT treatment every day, whereas children in the control group lived as usual without vision training. The primary outcome was the change in axial length at 6 months. Spherical equivalent refraction (SER) was included as a secondary outcome. Among 263 participants, 125 (47.5%) were male and 138 (52.5%) were female; the mean (SD) age was 10.3 (1.9) years (range, 6.1-15.6 years). A total of 227 patients (86.3%) completed the 6-month follow-up, including 102 in the intervention group and 125 in the control group. In the intervention group, the changes in axial length and SER at 6 months were 0.18 mm (95% CI, 0.16 to 0.20 mm) and -0.25 D (95% CI, -0.31 to -0.19 D), respectively. In the control group, the changes in axial length and SER at 6 months were 0.23 mm (95% CI, 0.21 to 0.25 mm) and -0.35 D (95% CI, -0.41 to -0.30 D), respectively. The differences in AL and SER between the 2 groups were significant (AL difference: -0.06 mm; 95% CI, -0.09 to -0.03; P < .001; SER difference: 0.10 D; 95% CI, 0.02 to 0.19; P = .02). No study-related adverse reactions were reported during follow-up. NVT is a safe and promising means to control myopia progression in children with good adherence. ClinicalTrials.gov Identifier: NCT05468775.

Artificial intelligence based glaucoma and diabetic retinopathy detection using MATLAB - retrained AlexNet convolutional neural network.

Glaucoma and diabetic retinopathy (DR) are the leading causes of irreversible retinal damage leading to blindness. Early detection of these diseases through regular screening is especially important to prevent progression. Retinal fundus imaging serves as the principal method for diagnosing glaucoma and DR. Consequently, automated detection of eye diseases represents a significant application of retinal image analysis. Compared with classical diagnostic techniques, image classification by convolutional neural networks (CNN) exhibits potential for effective eye disease detection. This paper proposes the use of MATLAB - retrained AlexNet CNN for computerized eye diseases identification, particularly glaucoma and diabetic retinopathy, by employing retinal fundus images. The acquisition of the database was carried out through free access databases and access upon request. A transfer learning technique was employed to retrain the AlexNet CNN for non-disease (Non_D), glaucoma (Sus_G) and diabetic retinopathy (Sus_R) classification. Moreover, model benchmarking was conducted using ResNet50 and GoogLeNet architectures. A Grad-CAM analysis is also incorporated for each eye condition examined. Metrics for validation accuracy, false positives, false negatives, precision, and recall were reported. Validation accuracies for the NetTransfer (I-V) and netAlexNet ranged from 89.7% to 94.3%, demonstrating varied effectiveness in identifying Non_D, Sus_G, and Sus_R categories, with netAlexNet achieving a 93.2% accuracy in the benchmarking of models against netResNet50 at 93.8% and netGoogLeNet at 90.4%. This study demonstrates the efficacy of using a MATLAB-retrained AlexNet CNN for detecting glaucoma and diabetic retinopathy. It emphasizes the need for automated early detection tools, proposing CNNs as accessible solutions without replacing existing technologies.

FBG-based three-dimensional micro-force sensor with axial force sensitivity-enhancing and temperature compensation for micro-forceps.

During retinal microsurgery, excessive interaction force between surgical instruments and intraocular tissue can cause serious accidents such as tissue injury, irreversible retinal damage, and even vision loss. It is essential to accurately sense the micro tool-tissue interaction force, especially for the Ophthalmic Microsurgery Robot. In this study, a fiber Bragg grating (FBG) three-dimensional (3-D) micro-force sensor for micro-forceps is proposed, which is integrated with the drive module as an end-effector and can be conveniently mounted onto the ophthalmic surgical robot. An innovative axial force sensitivity-enhancing structure is proposed based on the principles of flexure-hinge and flexible levers to overcome the low sensitivity of axial force measurement. A dual-grating temperature compensation method is adopted for axial force measurement, which considers the differential temperature sensitivity of the two FBGs. Three FBGs are arranged along the circumference of the guide tube in this study to measure transverse forces and compensate for effects caused by changes in temperature. The experimental results demonstrate that the micro-forceps designed in this study achieved a resolution of 0.13 mN for transverse force and 0.30 mN for axial force. The temperature compensation experiments show that the 3-D micro-force sensor can simultaneously compensate for temperature effects in axial and transverse force measurement.

Cancer-Associated Retinopathy (CAR) And Melanoma-Associated Retinopathy (MAR)

Cancer-associated retinopathy (CAR) and melanoma-associated retinopathy (MAR) are rare paraneoplastic syndromes in which antibodies are directed against retinal antigens, independent of primary tumor or metastasis, that can cause vision loss. The fact that these antigens differ according to different types of cancer causes the developing retinopathy and accordingly the symptoms to be heterogeneous and causing difficulties in diagnosis and treatment. The literature on this subject is limited with few reported case reports and case series. The lack of controlled clinical studies also makes it difficult for clinicians to manage these cases. Paraneoplastic syndromes are important because they can diagnose undiagnosed malignancies or indicate recurrence of treated malignancies. The appearance of the symptoms of CAR and MAR is of great importance for the prognosis of cancer, as it may precede cancer findings. In addition, with early diagnosis, irreversible retinal damage will be minimal. In this review, the pathophysiology, clinical findings and treatments of CAR and MAR are emphasized.

A lncRNA-encoded mitochondrial micropeptide exacerbates microglia-mediated neuroinflammation in retinal ischemia/reperfusion injury

As a common pathology of many ocular disorders such as diabetic retinopathy and glaucoma, retinal ischemia/reperfusion (IR) triggers inflammation and microglia activation that lead to irreversible retinal damage. The detailed molecular mechanism underlying retinal IR injury, however, remains poorly understood at present. Here we report the bioinformatic identification of a lncRNA 1810058I24Rik (181-Rik) that was shown to encode a mitochondrion-located micropeptide Stmp1. Its deficiency in mice protected retinal ganglion cells from retinal IR injury by attenuating the activation of microglia and the Nlrp3 inflammasome pathway. Moreover, its genetic knockout in mice or knockdown in primary microglia promoted mitochondrial fusion, impaired mitochondrial membrane potential, and reactive oxygen species (ROS) production, diminished aerobic glycolysis, and ameliorated inflammation. It appears that 181-Rik may trigger the Nlrp3 inflammasome activation by controlling mitochondrial functions through inhibiting expression of the metabolic sensor uncoupling protein 2 (Ucp2) and activating expression of the Ca2+ sensors S100a8/a9. Together, our findings shed new light on the molecular pathogenesis of retinal IR injury and may provide a fresh therapeutic target for IR-associated neurodegenerative diseases.

Extracellular vesicles of human diabetic retinopathy retinal tissue and urine of diabetic retinopathy patients are enriched for the junction plakoglo bin protein.

Diabetic Retinopathy (DR) is a potentially blinding retinal disorder that develops through the pathogenesis of diabetes. The lack of disease predictors implies a poor prognosis with frequent irreversible retinal damage and vision loss. Extracellular Vesicles (EVs) present a novel opportunity for pre-symptomatic disease diagnosis and prognosis, both severely limited in DR. All biological fluids contain EVs, which are currently being studied as disease biomarkers. EV proteins derived from urine have emerged as potential noninvasive biomarkers. In this study, we isolated EVs from DR retinal tissue explants and from DR patients' urine, and characterized the vesicles, finding differences in particle number and size. Next, we performed proteomic analysis on human explanted DR retinal tissue conditioned media, DR retinal EVs and DR urinary EVs and compared to normal human retinal tissue, retinal EVs, and urinary EVs, respectively. Our system biology analysis of DR tissue and EV expression profiles revealed biological pathways related to cell-to-cell junctions, vesicle biology, and degranulation processes. Junction Plakoglobin (JUP), detected in DR tissue-derived EVs and DR urinary EVs, but not in controls, was revealed to be a central node in many identified pathogenic pathways. Proteomic results were validated by western blot. Urinary EVs obtained from healthy donors and diabetic patient without DR did not contain JUP. The absence of JUP in healthy urinary EVs provide the basis for development of a novel Diabetic Retinopathy biomarker, potentially facilitating diagnosis.

Medications Damaging Retinal Pigment Epithelium and Photoreceptor Complex-1: Pathogenesis, Diagnosis, and Treatment (Chloroquine/hydroxychloroquine)

Hydroxychloroquine and chloroquine are frequently used in the treatment of rheumatic and parasitic diseases as a result of their immunomodulatory effects. Due to their high plasma distribution volumes, they cause irreversible side effects by accumulating in the tissues containing melanin following long-term use. Currently, these side effects can be detected before they reach advanced stages (bull’s eye maculopathy) thanks to new developments in diagnosis and imaging methods. Patients with concomitant tamoxifen use, impaired renal function, a dose of hydroxychloroquine greater than 5mg per kg per day or the dose of chloroquine greater than 2,3 mg per kg per day, older age, long-term use (10-25 years) have increased risk of retinopathy. Patients should be reviewed annually thereafter whilst on therapy and they should undergo imaging with optical coherence tomography (OCT), widefield fundus autofluorescence imaging (FAF), and 10-2 visual field testing at each monitoring visit. If the evidence of toxicity cannot be completely excluded patients should undergo multifocal electroretinography (mfERG). Of the tests used in the diagnosis of hydroxychloroquine/chloroquine retinopathy, mfERG has the highest sensitivity and specificity, followed by SD-OCT and 10-2 visual field tests, respectively. Once the precise signs of early retinopathy are detected, the decision to stop the medication should be taken in conjunction with prescribing physician. It should not be forgotten that retinopathy findings will progress even if the treatment is ceased. Following the screening, guidelines allow early detection of retinopathy before leading to irreversible retinal damage.

Characteristics and Potential Risk Factors of Hydroxychloroquine Retinopathy in Patients with Systemic Lupus Erythematosus: Focusing on Asian Population.

Purpose: Hydroxychloroquine (HCQ) would cause irreversible retinal damage, despite its pivotal role in treatment of systemic lupus erythematosus (SLE). This study aims to reassess the characteristics and risk factors of HCQ retinopathy. Methods: This study included patients with SLE who had used HCQ for >5 years and received ophthalmologic examinations during November 2017 to December 2020 in a tertiary hospital in Taiwan. Spectral-domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) were performed in all patients. Visual field assessment and/or multifocal electroretinography were done if suspicious findings were noted by SD-OCT or FAF. Clinical features and dosing details of HCQ were recorded by chart review. Results: Ninety-two patients were included, with the median duration of drug exposure of 11.2 years [interquartile range (IQR) 9.4-12.7 years], median daily dose of 6.9 mg/kg (IQR 6.1-7.7 mg/kg), and cumulative dose of 1,503.6 g (IQR 1,257.7-1,805.9 g). HCQ retinopathy was diagnosed in 10.9% of patients (10 of 92), and in 20.8% of patients (5 of 24) who complained about blurred vision. High myopia [odds ratio (OR) 5.03; 95% confidence interval (CI) 1.29-24.79; P = 0.03] and lower body weight (OR 0.88; 95% CI 0.78-0.97; P = 0.03) were significantly associated with HCQ retinopathy. Conclusions: Long-term HCQ users may suffer from retinal toxicity. Since there is no optimal substitute for HCQ, careful retinal evaluation is needed to avoid unnecessary drug discontinuation. In addition, an association between high myopia and HCQ retinopathy was noted. More investigation is needed to clarify this association.

Hemodynamic Retinal Artery Occlusion with Ipsilateral Carotid Artery Occlusion

Retinal artery occlusion (RAO) with hemodynamic changes including ipsilateral carotid stenosis/occlusion, reduced blood flow, and responsive compensatory flow, is considered as hemodynamic RAO. Multiple emboli are highly associated with hemodynamic RAO that embolism may raise from turbulence of stenotic carotid artery or accompany with compensatory flow via the collaterals. With compensatory flow, most hemodynamic RAO are transient and may have fair visual outcome. In this hemodynamic RAO, severe ischemic macular edema and devastating visual outcome is a result of multiple mechanisms. Ipsilateral ICA occlusion with decreased blood flow, inadequate primary compensatory flow to the eye, elongated duration of an alternative compensatory flow to re-establish ophthalmic circulations, and terminal infarctions of multiple emboli may all contribute the irreversible retinal damage and poor vision.

Hydroxychloroquine retinal toxicity- Can we do better with SD-OCT?

Hydroxychloroquine used in the management of connective tissue diseases also used to treat a wide spectrum of diseases. This disease-modifying anti-rheumatic drug can cause irreversible retinal damage and there are preferred practice guidelines for early screening to aid ophthalmologists and all those involved in the management of these patients. Spectral-Domain Optical Coherence Tomography (SD-OCT) currently an important tool in early detection of possible toxicity. Even with the current guideline-recommended 5mg/kg/day dosage, a baseline SD-OCT of the macula should be taken and repeated at 5 years. Many cross-sectional studies using SD-OCT have shown earlier retina damages, but none had monitored continuously from the beginning of Hydroxychloroquine usage. To evaluate sequential changes of the retina thickness in patients newly treated with hydroxychloroquine. We compared the mean central macular and Retinal Nerve Fiber Layer (RNFL) thickness pre, 3 months and 6 months post hydroxychloroquine using SD-OCT in order to find an association between them over the three time-points.33 previously healthy patients who were newly confirmed clinically and serologically with connective tissue disease planned for hydroxychloroquine who fulfilled the inclusion and exclusion criteria were recruited over 2 years. In consideration of selection criteria and drop-out rate, finally, 26 patients were included in the study.26 eyes of 26 patients (20 females and 6 males) were included in the study. The mean age was 33.92. The macula was significantly thinner (P&amp;#60;0.05) at superior (P&amp;#60;0.032), temporal (P&amp;#60;0.025), and inferior (P&amp;#60;0.016) parafoveal areas. RNFL showed significantly thinning at the temporal quadrant (P&amp;#60;0.041). Further analysis showed significant occurrences of parafoveal inferior thinning at 3 (P&amp;#60;0.035) and 6 (P&amp;#60;0.032) months. Correlation analysis between parafoveal thinning and the mean optic disc RNFL showed a significant result (p =0.004, r=0.55). The mean optic disc RNFL thickness significantly affected lesser (p =0.004, r =0.302) than the perifoveal area (p =0.001, r =0.784) when compared to the typical parafoveal pattern of thinning in this toxicity.There is a need for an earlier repetition of SD-OCT imaging before 5 years to detect potential toxicity. Involvement of RNFL requires further investigation and monitoring.

Ferrostatin-1 attenuates ferroptosis and protects the retina against light-induced retinal degeneration

Degenerative retinal diseases, including age-related macular degeneration, are serious diseases that may lead to irreversible retinal neuron damage and permanent vision impairment. There are currently no effective treatments for these diseases due to our incomplete understanding of the underlying pathological mechanisms. Ferroptosis, a newly identified iron-dependent mode of cell death, is implicated in various diseases. However, it is unknown whether ferroptosis is involved in light-induced retinal degeneration. In this study, we found that light exposure significantly reduced the viability of photoreceptor cells in vitro and induced pro-ferroptotic changes, including iron accumulation, mitochondrial shrinkage, glutathione depletion, increased malondialdehyde (MDA), and decreased protein expression of SLC7A11 and GPX4. The effects of light exposure on ferroptosis were attenuated by ferrostatin-1. Consistently, the results of in vivo studies demonstrated that ferrostatin-1 protected against light-induced ferroptosis. And it exerted therapeutic effects by inhibiting neuroinflammation and prevented the effects of light exposure on the structure and function of the retina. The findings reveal an important role of ferroptosis in the pathogenesis of light-induced retinal degeneration and suggest that ferroptosis may be a novel treatment target for preventing retinal degeneration.

The Role of Lipoxidation in the Pathogenesis of Diabetic Retinopathy.

Lipids can undergo modification as a result of interaction with reactive oxygen species (ROS). For example, lipid peroxidation results in the production of a wide variety of highly reactive aldehyde species which can drive a range of disease-relevant responses in cells and tissues. Such lipid aldehydes react with nucleophilic groups on macromolecules including phospholipids, nucleic acids, and proteins which, in turn, leads to the formation of reversible or irreversible adducts known as advanced lipoxidation end products (ALEs). In the setting of diabetes, lipid peroxidation and ALE formation has been implicated in the pathogenesis of macro- and microvascular complications. As the most common diabetic complication, retinopathy is one of the leading causes of vision loss and blindness worldwide. Herein, we discuss diabetic retinopathy (DR) as a disease entity and review the current knowledge and experimental data supporting a role for lipid peroxidation and ALE formation in the onset and development of this condition. Potential therapeutic approaches to prevent lipid peroxidation and lipoxidation reactions in the diabetic retina are also considered, including the use of antioxidants, lipid aldehyde scavenging agents and pharmacological and gene therapy approaches for boosting endogenous aldehyde detoxification systems. It is concluded that further research in this area could lead to new strategies to halt the progression of DR before irreversible retinal damage and sight-threatening complications occur.

Laser Pointer: A Possible Risk for the Retina.

In recent years, an increasing incidence of laser pointer-associated retinal injuries has been observed, likely due to easy access to incorrectly classified laser pointers, their labelling as toys, and lack of awareness concerning the associated risk. Laser pointer exposure can lead to irreversible retinal damage and associated vision loss, depending on the wavelength, radiation power, duration of exposure, localization, and spot size. Pronounced retinal laser damage is especially seen in children and teenagers. The structural appearance of retinal laser pointer damage varies and, in some cases, may be a diagnostic challenge. Besides often subtle findings on optical coherence tomography examination, characteristic alterations on near-infrared autofluorescence imaging may be valuable for the diagnosis of retinal laser pointer injuries and for differentiating other retinal lesions with similar appearance. The increase in laser pointer injuries indicates that regulatory actions and increased public awareness are required regarding the dangers of laser pointers.

Behçet's Uveitis: Current Diagnostic and Therapeutic Approach

Behçet’s disease is a chronic, multisystem inflammatory disorder characterized by relapsing inflammation. Although its etiopathogenesis has not yet been clarified, both the adaptive and innate immune systems, genetic predisposition, and environmental factors have all been implicated. It is more frequent and more severe in males in the third and fourth decades of life. The eye is the most frequently involved organ in the course of the disease. Ocular involvement (Behçet’s uveitis) is characterized by bilateral recurrent non-granulomatous panuveitis and occlusive retinal vasculitis. Recurrent inflammatory episodes in the posterior segment may lead to permanent vision loss due to irreversible retinal damage and complications such as macular scarring, macular atrophy, and optic atrophy. Early and aggressive immunomodulatory treatment and the use of biologic agents when needed are crucial for preventing recurrences and improving visual prognosis.

Chloroquine and Hydroxychloroquine Retinal Toxicity Consideration in the Treatment of COVID-19.

The proposed doses of chloroquine (CQ) and hydroxychloroquine (HCQ) for treatment of COVID-19 (1000 mg/day for 10 days, CQ; 800 mg first day then 400 mg/day for 5 days, HCQ) in many guidelines worldwide, are considerably higher than the maximum recommended daily safe doses of both agents (≤2.3 mg/kg/day, CQ; ≤5.0 mg/kg/day, HCQ) for development of retinal toxicity. Irreversible retinal damage can occur if the exposure to the safe doses is >5 years. It is not known whether exposure to high doses over a short period of time can also cause the damage. We recommend that before prescribing CQ or HCQ, history of ocular disease should be obtained to avoid the prescription if appropriate. If either agent is to be used, routine baseline ocular examination is not absolutely necessary. Patients who do not have ocular disease should also be informed about the potential risk of retinal toxicity. Both agents, however, have not yet been proven to be beneficial to COVID-19.

Development of visual acuity under hyperbaric oxygen treatment (HBO) in non arteritic retinal branch artery occlusion

Nonperfusion of retinal tissue due to arterial occlusion leads inevitably to mostly irreversible retinal damage. Until today no evidence-based treatment exists. Inhalation of 100% oxygen at high atmospheric pressure causes an increased solubility of oxygen in the blood that helps the retinal tissue to survive through diffusion in case of an artery occlusion till vascular recanalization occurs. Hence the purpose of this study is to compare the visual outcome in patients with retinal branch artery obstruction treated with hyperbaric oxygen versus patients treated with hemodilution only. Non-randomized, monocentric, retrospective study. Patients with diagnosis of non-arteritic retinal branch artery occlusion (BRAO) treated with hyperbaric oxygen therapy between 1997 and 2017. Exclusion criteria were central retinal artery occlusion, presence of a cilioretinal artery and arteritic cases. The control group was matched based on visual acuity (VA) at admission, age, and delay between symptoms and beginning of clinical care. The control group and the matching oxygen group contained 14 patients each. Initial VA in the matched HBO group was 0.18 ± 0.19 and 0.23 ± 0.19 in the control group (p = 0.57). Final VA at discharge was 0.69 ± 0.29 in the matched oxygen group and 0.32 ± 0.23 in the control group (p = 0.0009). HBO-treated patients had a significant visual increase compared with the control group. The most common comorbidities were arterial hypertension and vascular sclerosis. HBO treatment appears to have a beneficial effect on visual outcome in patients with retinal branch artery occlusion. HBO treatment could be a rescue therapy at an early stage of BRAO, especially to bridge the time of a potential reperfusion. However, further, prospective, randomized clinical trials are required to verify this assumption.

Abstract WP69: Guideline-Based Intravenous rPA for Central Retinal Artery Occlusion: A Case Series and Systematic Review

Introduction: Central retinal artery occlusion (CRAO) rapidly leads to irreversible retinal damage with spontaneous visual recovery in only 10-20%. IV tPA may improve visual outcomes in CRAO, but protocols are heterogeneous. Deviation from acute ischemic stroke guidelines (AISG) for IV tPA is associated with symptomatic intracranial hemorrhage (sICH). Our study characterizes outcomes for CRAO patients treated with IV tPA per AISG to better define the risk and benefit. Methods: We executed a systematic literature review (SLR) of IV tPA for CRAO in Cochrane, Embase, and Medline. Subsequently, we performed a retrospective chart review at two local academic hospitals. All CRAO patients identified locally or via SLR who were treated with IV tPA per AISG were included in our study. Primary outcomes included improvement in visual acuity (VA), defined as ≥0.3 logMAR, and safety, specifically sICH. Results: Our SLR yielded 136 articles of which 19 were eligible. 137 total CRAO patients were identified, 32 (23%) of whom received IV tPA per AISG. 13 additional CRAO patients treated per AISG were identified locally (Table 1A). Of these 45 cases, VA was reported in 39, with improvement in 64%, no change in 28%, and worsening in 8%. The risk of sICH was 2.2% (n=1) (Table 1B). The case of sICH occurred locally, with hemorrhage adjacent to 2 chronic appearing infarcts. Post-sICH it was impossible to determine radiographically whether a component of his infarct may have been subacute. Interestingly, in our local cases, clinically silent diffusion restriction was evident on MRI in 6 patients (46%). Conclusion: Our study suggests that IV tPA administered per AISG may improve visual outcomes in comparison to the natural history of CRAO, however, the rate of sICH was not inconsequential. Additionally, our case series includes the first reported sICH in a CRAO patient administered IV tPA per AISG. Randomized studies are warranted to assess the efficacy and safety of IV tPA administered per AISG in CRAO.

Bilateral idiopathic retinal vasculitis following coxsackievirus A4 infection: a case report

BackgroundCoxsackieviruses are members of a group of viruses called the enteroviruses, which may cause respiratory and gastrointestinal symptoms, erythema, meningoencephalitis, myocarditis, pericarditis, and myositis. Unilateral acute idiopathic maculopathy caused by coxsackievirus A16 has been associated with hand, foot, and mouth disease, but only a few reports describe retinitis associated with coxsackievirus serotype B3 or B4. We report a case of bilateral multifocal obstructive retinal vasculitis that developed after coxsackievirus A4 infection.Case presentationA 60-year-old woman was referred to our department with bilateral visual disturbance that developed following flu-like symptoms. At the initial examination, best corrected visual acuity was 20/200 in the right eye and 20/50 in the left eye. The critical flicker frequency (CFF) was 23 Hz in the right eye and 27 Hz in the left eye. Fine white keratic precipitates with infiltrating cells were presented in the anterior chamber of both eyes, and multifocal retinal ischemic lesions were observed in the macula and posterior pole of both eyes. The retinal lesions corresponded with scotomas observed in Goldmann visual field test. On spectral domain-optical coherence tomography (SD-OCT), retinal lesions were depicted as hyper-reflective regions in the inner retina layers in both eyes, and disruption of ellipsoid line in the left eye., Fluorescein angiography exhibited findings indicative of multifocal obstructive retinal vasculitis. The patient had a history of current hypertension treated with oral therapy and glaucoma treated with latanoprost eye drops. Blood test for coxsackievirus antibody titers revealed that A4, A6, A9, B1, B2, B3, and B5 were positive (titers: 8–32). Abdominal skin biopsy of necrotic tissue suggested vascular damage caused by coxsackievirus. The general symptoms improved after 6 weeks, and the multifocal retinal ischemic lesions were partially resolved with residual slightly hard exudates. Only coxsackievirus A4 antibody titer increased from 4 to 32-fold after 14 months. However, hyper-reflective regions and disruption of the inner retinal layers on SD-OCT persisted especially in the right eye, and residual paracentral scotoma was observed in the right eye.ConclusionThe present case suggests that coxsackievirus A4 causes bilateral multifocal obstructive retinal vasculitis with irreversible inner retinal damage.

Targeted Multifunctional Lipid ECO Plasmid DNA Nanoparticles as Efficient Non-viral Gene Therapy for Leber's Congenital Amaurosis.

Development of a gene delivery system with high efficiency and a good safety profile is essential for successful gene therapy. Here we developed a targeted non-viral delivery system using a multifunctional lipid ECO for treating Leber’s congenital amaurosis type 2 (LCA2) and tested this in a mouse model. ECO formed stable nanoparticles with plasmid DNA (pDNA) at a low amine to phosphate (N/P) ratio and mediated high gene transfection efficiency in ARPE-19 cells because of their intrinsic properties of pH-sensitive amphiphilic endosomal escape and reductive cytosolic release (PERC). All-trans-retinylamine, which binds to interphotoreceptor retinoid-binding protein (IRBP), was incorporated into the nanoparticles via a polyethylene glycol (PEG) spacer for targeted delivery of pDNA into the retinal pigmented epithelium. The targeted ECO/pDNA nanoparticles provided high GFP expression in the RPE of 1-month-old Rpe65−/− mice after subretinal injection. Such mice also exhibited a significant increase in electroretinographic activity, and this therapeutic effect continued for at least 120 days. A safety study in wild-type BALB/c mice indicated no irreversible retinal damage following subretinal injection of these targeted nanoparticles. All-trans-retinylamine-modified ECO/pDNA nanoparticles provide a promising non-viral platform for safe and effective treatment of RPE-specific monogenic eye diseases such as LCA2.