Neurosensory Retina Research Articles

Traumatic Maculopathies Associated with Closed-Globe Injury

Traumatic maculopathies due to closed-globe injury are commotio retinae (Berlin’s edema), choroidal rupture, traumatic macular hole, retinitis sclopetaria, shaken baby syndrome, Valsalva retinopathy, and Purtscher retinopathy. The main pathology in commotio retinae is in the outer retinal layers and usually resolves spontaneously. Blunt eye traumas coming from the anterior aspect can cause choroidal ruptures. These are mainly due to the rupture of inelastic Bruch membrane and adjacent structures. If they involve fovea, visual loss can occur. Late choroidal neovascularisation may develop in 1/10 of the cases. Traumatic macular holes develop in less than 2% of the blunt ocular traumas. Early macular holes result from tangential traction whereas late holes from anteroposterior vitreoretinal traction. They can be closed spontaneously within 4 months, especially in young patients. Retinitis sclopetaria is rare. It results from high-velocity pellets that hit but do not penetrate the globe. Shock waves can cause the rupture of the choroid and overlie the neurosensory retina. The shaken baby syndrome is a result of the violence in the family. It must be reported to the police. Retinal hemorrhages, cotton wool spots, and hemorrhagic retinoschisis areas are the prominent features. The sudden increase in intrathoracic or abdominal pressure may lead to the rupture of the retinal capillaries and usually a sub-internal limiting membrane hemorrhage in Valsalva retinopathy. If it is larger than 3-disc diameters and persists for more than 3 weeks; it may be drained into vitreous with an Nd-YAG laser. Purtscher retinopathy is an occlusive microvasculopathy resulting from severe head trauma or compression injuries of the thorax. Intraretinal hemorrhages, geometric white areas (Purtscher flecken), and cotton wool spots are typical features. Usually fades within 1-2 months. Medicolegal aspects as well as ocular and systemic associations are also important in closed globe injuries and should not be neglected.

Anti-inflammatory effect of glucagon-like Peptide-1 receptor agonist on the neurosensory retina in an acute optic nerve injury rat model

PurposeTo explore the possibility of using glucagon-like peptide-1 receptor agonist (GLP-1RA) as a new treatment for neuroinflammation, by analyzing retinal pathological changes in an optic nerve crush rat model. MethodsEight-week-old male Sprague-Dawley rats were divided into lixisenatide (LIX, n = 10), traumatic control (T-CON, n = 10), and normal control (n = 5) groups. The optic nerves of left eyes in the LIX and T-CON groups were crushed in a standardized manner. The LIX group was treated with subcutaneous injections of lixisenatide (200 μg/kg/day) for 5 days. One week after initiating treatment, quantitative polymerase chain reaction, Western blot, and immunohistochemistry analyses were performed on the retinal tissues of each group to identify inflammatory markers. ResultsThe LIX group showed significantly lower mRNA levels of interleukin 1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), thioredoxin interacting protein (TXNIP), and glial fibrillary acidic protein (GFAP) than the T-CON group. Also, the LIX group exhibited decreased TXNIP and GFAP expression compared with the T-CON group, and similar expression to the normal control group, according to Western blot analysis. Significantly increased immunohistochemistry staining of Brn3a and decreased TUNEL staining were seen in the LIX group compared with the T-CON group, indicating that lixisenatide contributes to retinal ganglion cell survival in cases of acute optic nerve injury. ConclusionsNeuroinflammation was significantly reduced in lixisenatide-treated retinas compared with untreated retinas in our acute optic nerve injury rat model. The neuroprotective effect of lixisenatide indicates that it can serve a new treatment option against clinically intractable traumatic optic neuropathy.

Characterization and diagnosis of retinoschisis and schisis detachments using spectral domain optical coherence tomography.

To characterize retinoschisis in a large series using spectral domain optical coherence tomography (SD-OCT), including rates of schisis detachment and macular involvement in cases of peripheral retinoschisis. In this retrospective, cross-sectional, descriptive study, consecutive patients with diagnosis of retinoschisis in at least one eye were identified using billing codes between January 2012 and May 2021. Charts were reviewed to verify diagnosis of retinoschisis or schisis detachment. SD-OCT and clinical examination was used to identify frequency of macular schisis, peripheral schisis, and schisis detachment, and characteristics of retinoschisis including frequency of inner and outer wall breaks, distribution of layers split, and location of involvement of peripheral pathology. SD-OCT images of insufficient quality were excluded from the pertinent analysis. 281 eyes of 191 patients were included. 195 (69.4%) eyes had peripheral retinoschisis, 15 (5.3%) had schisis detachment, 66 (23.5%) had macular retinoschisis alone, and 5 (1.8%) had combined macular and peripheral retinoschisis. Of the eyes without macular retinoschisis, 7.0% had schisis detachment. Of the remainder, 4 (2.1%) had inner wall breaks, and 24 (12.3%) had outer wall breaks. In eyes with peripheral retinoschisis, splitting occurred in the outer plexiform layer in 58.9%, the retinal nerve fiber layer in 8.9%, a combination of layers in 26.8%, and indeterminate in 5.4%. Location of peripheral involvement was inferotemporal in 58.5%, superotemporal in 14.1%, temporal in 13.7%, and inferior in 12.2%. SD-OCT helped to identify the presence of schisis detachment and breaks, confirmed diagnosis in challenging cases, and demonstrated the layer of splitting within the neurosensory retina. This series represents the largest such study to date.

In Vivo Imaging of Retinal and Choroidal Morphology and Vascular Plexuses of Vertebrates Using Swept-Source Optical Coherence Tomography.

PurposeTo perform in vivo evaluation of the structural morphology and vascular plexuses of the neurosensory retina and choroid across vertebrate species using swept-source optical coherence tomography (SS-OCT) and SS-OCT angiography (SS-OCTA) imaging.MethodsA custom-built SS-OCT system with an incorporated flexible imaging arm was used to acquire the three-dimensional (3D) retinal OCT and vascular OCTA data of five different vertebrates: a mouse (C57BL/6J), a rat (Long Evans), a gray short-tailed opossum (Monodelphis domestica), a white sturgeon (Acipenser transmontanus), and a great horned owl (Bubo virginianus).ResultsIn vivo structural morphology of the retina and choroid, as well as en face OCTA images of retinal and choroidal vasculature of all species were generated. The retinal morphology and vascular plexuses were similar between rat and mouse, whereas distinct choroidal and paired superficial vessels were observed in the opossum retina. The retinal and vascular structure of the sturgeon, as well as the pecten oculi and overlying the avascular and choroidal vasculature in the owl retina are reported in vivo.ConclusionsA high-quality two-dimensional and 3D in vivo visualization of the retinal structures and en face visualization of the retina and choroidal vascular plexus of vertebrates was possible. Our studies affirm that SS-OCT and SS-OCTA are viable methods for evaluating the in vivo retinal and choroidal structure across terrestrial, aquatic, and aerial vertebrates.Translational RelevanceIn vivo characterization of retinal morphology and vasculature plexus of multiple species using SS-OCT and SS-OCTA imaging can increase the pool of species available as models of human retinal diseases.

A Review of Central Serous Chorioretinopathy: Clinical Presentation and Management.

Central serous chorioretinopathy (CSC) may be understood as a disease of the chorioretina with the serous detachment of the neurosensory retina, which is secondary to single or multiple localized defects in retinal pigment epithelium (RPE). CSC is one of the common forms of loss of vision, usually seen in people who do belong to the working-age group. The most common symptoms are blurring of vision, usually unilateral and which is perceived as a scotoma in the center of the field of vision with associated metamorphopsia and micropsia. The risk factor associated with CSC is psychosocial stress, type A personality, pregnancy, and hypercortisolism. Normal vision is often restored within a span of a few months. After around three months, if the resolution of acute CSC did not change or, let us say, in the case of CSC that is chronic, one should consider treatment. In acute CSC, to resolve symptoms, especially in individuals who work in a field where eyesight is of utmost importance, for example, pilots, focal photocoagulation of leaking RPE lesions can be performed. CSC is a prototype cause of serous neuroretinal detachment, which involves the fovea. CSC symptoms reflect the separation between the RPE and the photoreceptors and the bullous distension of the foveal retina. The effect of therapy as such on the long-term outcome of vision visual is not sufficiently documented. The management would largely be dependent on the appropriate diagnosis made based on clinical presentations, and thus it becomes very much necessary to have knowledge about the same and counsel the patient regarding the association between stress and disease pathology. In acute CSC, retinal photocoagulation is successful to a good extent in eliminating or reducing the leakage of RPE and hence it induces resolution of the serous detachment. This review article is made to make sure the reader is updated about the various clinical and management aspects of CSC by providing a comprehensive idea that is obtained from various well-acknowledged databases across the globe on CSC.

Commentary: Usage of intravitreal steroids in endophthalmitis: Horns of a dilemma

The usage of steroids intravitreally along with antimicrobials for endophthalmitis management has been marred with controversy for decades. To a large extent, management of endophthalmitis has been based on physician discretion and has a lot of variability between cases. The rationale behind steroids/anti-inflammatory agents is that endophthalmitis leads to severe inflammation and bystander damage to intraocular tissues, especially the neurosensory retina, resulting in irreversible functional changes. Suppressing this inflammation may help reduce the irreversible damage and shorten the overall disease course. It is not well understood whether the damage to the visual function is due to the infectious agent or the immune response developed by the host in response to it. There is no unanimous understanding regarding whether steroids have any definite role in visual improvement as demonstrated by this metanalysis, and previous reports as well.[1] The current article evaluated studies dealing with bacterial endophthalmitis alone. Considering fungal endophthalmitis, there is even lesser amount of evidence regarding the status of steroids, as steroids are believed to flare up intraocular pathogens. One way to approach this conundrum is to consider steroids once an initial dose of intravitreal antimicrobials has been given and/or vitrectomy has been done to reduce the microbial load. Then, if the patient is undergoing further intravitreal injections, intravitreal steroids can be considered. However, steroids may have a definite role in preserving the anatomical integrity during initial endophthalmitis management, preventing outcomes such as phthisis bulbi or requirement of evisceration.[2] The inconsistencies in management rationale, type of outcomes reported, and follow-up protocols in previous studies make a uniform consensus difficult—more so because quantifying resolution or a successful management of endophthalmitis is not standardized. Steroids may reduce tissue inflammation in the initial period, which in turn can reduce the chances of eyes requiring further vitrectomies or IOL explantation procedures. Another point to ponder is that the older evidence of intravitreal steroids is from days when an initial intravitreal regimen of antibiotics with or without steroids with additional injections would be considered followed by a period of observation. A decision of vitrectomy would be taken after noting the resolution pattern and based on physician discretion. However, with complete and early vitrectomy, as is becoming the norm gradually, after the organism load has been reduced, intravitreal steroids may also be considered in the retreatment regimens.[3] The biggest gray zone is for cases of fungal endophthalmitis, where no clear evidence is available due to extreme variability in clinical presentations. Authors have noted that visual outcomes may be better in fungal endophthalmitis with the usage of systemic or topical steroids under a cover of antifungal therapy.[4] However, the sensitivity of the fungi to the antifungal agent and the timing and dosage of steroids must be considered before starting the same. Currently, although we have an armamentarium of drugs and surgical modalities, the outcomes of endophthalmitis remain poor because of unknown host and organism related factors, which cannot be treated using conventional methods. Experimental studies in animals have shown that infectious endophthalmitis can induce the expression of cytokines, chemokines, and apoptotic factors. Recently, authors have also studied inflammatory changes in the vitreous taken from endophthalmitis patients and tried to identify factors that can predict the clinical outcomes of the disease.[5678] Apoptotic proteins such as Bax and Fas expression peaks at 48 h after initial endophthalmitis onset, and apoptotic rate peaks at 72 h under experimental conditions.[9] Many such host innate immune pathways are under research to try and target for endophthalmitis management in addition to antimicrobials. Reducing the concentrations of individual inflammatory mediators might limit the bystander damage to tissues while allowing a more favorable wound healing response along with neuroprotection. A TLR2 agonist, Pam3Cys, has been explored as a molecule which attenuates clinical inflammation, reduces bacterial load in retina, and preserves retinal architecture with electroretinogram in mice retina.[10] Anti-TNFa therapy may also have role in improving endophthalmitis outcomes.[11] Other possible drug targets in stage of development are anti IL6, anti IL1beta, anti IL8, etc., Scientists have also employed macrophage membrane-coated nanosponges as decoys to bind excess cytokines and chemokines in the vitreous to prevent cytotoxicity.[12] Further studies are needed to identify molecules that can help in reducing inflammation in severe and fulminating endophthalmitis cases and salvage such eyes toward both optimum anatomical and functional outcomes.

Resolution of Bilateral Exudative Retinal Detachment Secondary to Renal Hypertension with Systemic Management

Exudative retinal detachment (ERD) is an ocular condition, which develops from pathological conditions that disrupt the integrity of blood-retinal barrier due to fluid accumulation in sub retinal space or under neurosensory retina. Exudative retinal detachment is typically associated with inflammatory, infectious, neoplastic, and vascular pathological conditions. We report the management of bilateral exudative retinal detachment in young patients secondary to Renal Hypertension.

Hyperoxia‐Induced Preretinal Membrane Formation and Retinal Detachment in the Mouse

BackgroundRetinal detachment (RD) is a vision‐threatening consequence of several conditions including retinopathy of prematurity (ROP). Numerous studies have established the connection of high oxygen concentration altering retinal development in preterm infants, leading to RD and blindness in later stages. The goal of this study was to develop a reproducible, non‐invasive model mouse of human ROP that could be used to study the cellular events leading to the formation of tractional preretinal membranes and RD.HypothesisPlacing C57BL/6J mice in hyperoxic conditions for one week starting at birth will induce a non‐traumatic sequence of retinopathy leading to tractional RD that mimics the pathophysiology of detachment seen in ROP.MethodsC57BL/6J newborn mice were placed into a hyperoxic environment (65% oxygen saturation) for 7 days then reared in ambient air. Retinas were observed at weeks 4, 5, and 7 via spectral‐domain optical coherence tomography (OCT). Eyes were processed for histology and immunostaining for the myofibroblast marker alpha‐smooth muscle actin (α‐SMA).ResultsFour weeks after birth, 100% of mice placed in hyperoxia exhibited retinal blebs, 91% had developed preretinal membranes, and 9% had RD. At 5 weeks, 100% and 27% had preretinal membranes and RD, respectively. At week 7, the number of mice with RD increased to 33%. Preretinal membranes arose at the surface of the retina above the optic nerve head. RD occurred between the neurosensory retina and the underlying retinal pigment epithelium. Myofibroblasts were detected with the antibody to α‐SMA in the preretinal membranes and above areas of RD.ConclusionThe hyperoxia‐induced retinopathy model was confirmed to induce retinal pathology in newborn mouse pups. Retinal pathology progressed during a 7‐week time period (i.e. retinal blebs to preretinal membranes and folds to retinal detachment). This noninvasive model replicates the oxygen‐induced retinopathy seen in human ROP. The model is useful for investigating the origin of cells that contribute to the formation of tractional retinopathy, especially PRMs and RD. The presence of α‐SMA‐positive cells overlying areas of retinopathy suggests the contractile property of myofibroblasts induces tractional RD.

Melatonin prevents experimental central serous chorioretinopathy in rats.

Central serous chorioretinopathy (CSC) is a vision-threatening disease with no validated treatment and unclear pathogenesis. It is characterized by dilation and leakage of choroidal vasculature, resulting in the accumulation of subretinal fluid, and serous detachment of the neurosensory retina. Numerous studies have demonstrated that melatonin had multiple protective effects against endothelial dysfunction, vascular inflammation, and blood-retinal barrier (BRB) breakdown. However, the effect of melatonin on CSC, and its exact pathogenesis, is not well understood thus far. In this study, an experimental model was established by intravitreal injection of aldosterone in rats, which mimicked the features of CSC. Our results found that melatonin administration in advance significantly inhibited aldosterone-induced choroidal thickening and vasodilation by reducing the expression of calcium-activated potassium channel KCa2.3, and attenuated tortuosity of choroid vessels. Moreover, melatonin protected the BRB integrity and prevented the decrease in tight junction protein (ZO-1, occludin, and claudin-1) levels in the rat model induced by aldosterone. Additionally, the data also showed that intraperitoneal injection of melatonin in advance inhibited aldosterone-induced macrophage/microglia infiltration, and remarkably diminished the levels of inflammatory cytokines (interleukin-6 [IL-6], IL-1β, and cyclooxygenase-2), chemokines (chemokine C-C motif ligand 3, and C-X-C motif ligand 1), and matrix metalloproteinases (MMP-2and MMP-9). Luzindole, as the nonselective MT1 and MT2 antagonist, and 4-phenyl-2-propionamidotetraline, as the selective MT2 antagonist, neutralized the melatonin-induced inhibition of choroidal thickening and choroidal vasodilation, indicating that melatonin might exert the effects via binding to its receptors. Furthermore, the IL-17A/nuclear factor-κB signaling pathway was activated by intravitreal administration of aldosterone, while it was suppressed in melatonin-treated in advance rat eyes. This study indicates that melatonin could serve as a promising safe therapeutic strategy for CSC patients.

Frequency of cystoid macular edema and vitreomacular interface disorders in genetically solved syndromic and non-syndromic retinitis pigmentosa.

Retinitis pigmentosa (RP) corresponds to a group of inherited retinal disorders where progressive rod-cone degeneration is observed. Cystoid macular edema (CME) and vitreomacular interface disorders (VMID) are known to complicate the RP phenotype, challenging an age-old concept of retained central visual acuity. The reported prevalence of these changes varies greatly among different studies. We aim to describe the frequency of CME and VMID and identify predictors of these changes in a cohort of Caucasian patients with genetically solved syndromic (sRP) and non-syndromic RP (nsRP). Cross-sectional study of patients with genetically solved sRP or nsRP. Genetic testing was clinically oriented in all probands and coordinated by a medical geneticist. The presence/absence of CME and VMIDs such as epiretinal membrane (ERM), vitreomacular traction (VMT), lamellar hole (LH), macular hole (MH), and macular pseudohole (MPH), and the integrity of the neurosensory retina and retinal pigment epithelium were evaluated in individual macular SD-OCT b-scans. Mixed-effects regression analysis models were used to identify significant predictors of BCVA, CME, and VMID. Significance was considered at α < 0.05. We included 250 eyes from 125 patients. Mean age was 44.9 ± 15.7years and 55.2% were male. Eighty-eight patients had nsRP and 37 had sRP. Median BCVA was 0.5 (0.2-1.3) logMAR. CME was found in 17.1% of eyes, while ERM was found in 54.3% of eyes. The frequency of CME (p = 0.45) and ERM (p = 0.07) did not differ between sRP and nsRP patients, nor across different inheritance patterns. Mixed-effects univariate linear regression identified age (p = 0.04), cataract surgery (p < 0.01), and loss of integrity of outer retinal layers (p < 0.01) as significant predictors of lower visual acuity, while increased foveal thickness (p < 0.01) and the presence of CME (p = 0.04) were predictors of higher visual acuity. On mixed-effects multivariable analysis, only increased foveal thickness was significantly associated with better visual acuity (p < 0.01). We found that the burden of ERM and CME in RP patients is high, highlighting the importance of screening for these potentially treatable conditions to improve the quality of life of RP patients.

The Anatomy, Physiology, and Histology of Optic Nerve

The optic nerve (Nervus opticus) is the second of the 12 cranial nerves and is considered to be a part of the central nervous system. It carries visual information from the neurosensory retina to the occipital cortex. The nerve consists of the axons of retinal ganglion cells (RGCs). These axons extend in an organized pattern from the RGC soma to the lateral geniculate nucleus where the neuron's synapse. The nerve is subdivided into fascicles by connective tissue and glial septa, and it is surrounded by cerebrospinal fluid. The optic nerve has intraocular, intraorbital, intracanalicular, and intracranial parts and a length of approximately 50 mm. The central retinal artery, the Zinn-Haller circle formed by the short posterior ciliary artery extensions, and pial vessels take part in the blood supply of the nerve.

Vascular Analysis of Type 1, 2, and 3 Macular Neovascularization in Age-Related Macular Degeneration Using Swept-Source Optical Coherence Tomography Angiography Shows New Insights into Differences of Pathologic Vasculature and May Lead to a More Personalized Understanding.

Background: The clinical appearance of macular neovascularization (MNV) in age-related macular degeneration (nAMD) varies widely, but so far, this has had no relevance in terms of therapeutic approaches or prognosis. Therefore, our purpose was to investigate if and which differences exist in the vascular architecture of MNV and to quantify them. Methods: In 90 patients with newly diagnosed nAMD, MNV was identified by means of optical coherence tomography angiography (OCTA), and automated quantitative vascular analysis was carried out. The analyzed vascular parameters were area, flow, fractal dimension (FD), total vascular length (sumL), number of vascular nodes (numN), flow, and average vessel caliber (avgW). The current classification of MNVs divides them according to their localization into type 1 (grown from the choroid below the RPE), type 2 (grown from the choroid through RPE), and type 3 (grown from the retina toward the RPE). We compared the analyzed vascular parameters of each of the three MNV types. Kruskal–Wallis test was applied, Dunn test was performed for post hoc analysis, and for pairwise comparison, p-values were adjusted using Bonferroni comparison. Results: Regarding the MNV area, there was no significant difference between types 1 and 2, but type 3 was significantly smaller than types 1 and 2 (p < 0.00001). For FD, types 1 and 2 did not differ significantly, but again, type 3 was lower than type 1 and 2 (p < 0.00001). The numN were significantly higher in types 1 and 3 than in 2 (p < 0.005), but not between types 1 and 3. No significant differences were found between MNV types for flow. As for sumL, types 1 and 2 did not differ significantly, but type 3 was significantly lower than types 1 and 2 (p < 0.00001). For avgW, there was no significant difference between types 1 and 2 or between types 2 and 3, but type 3 was significantly larger than type 1 (p < 0.05). Conclusions OCTA yields detailed information on the vascular morphology of MNV in patients with nAMD and is able to show differences among types 1, 2, and 3. Especially comparing types 1 and 2 with type 3 reveals significant differences in area, FD, sumL, and numN. One explanation could be the similar pathogenesis of types 1 and 2 with their origin in the choroid and their growth towards the retinal pigment epithelium (RPE), whereas type 3 originates in the deep capillary plexus. Between types 1 and 2, however, only the numN differ significantly, which could be due to the fact that type 1 spreads horizontally below the RPE and, thus, display more vascular branching, while type 2 grows more vertically through the RPE and under the neurosensory retina. Detailed information about the pathologic vasculature is important for proper monitoring of the disease and to assess the efficacy of medication, especially with regard to new substances. This should be taken into consideration in future studies.

Fluctuations in central foveal thickness and association with vision outcomes with anti-VEGF therapy for nAMD: HARBOR post hoc analysis

ObjectiveTo evaluate correlations between variability in central foveal thickness (CFT) and vision with ranibizumab in a HARBOR post hoc analysis.Methods and analysisPatients with neovascular age-related macular degeneration (nAMD; N=1097) received...

Of men and mice: Human X-linked retinoschisis and fidelity in mouse modeling.

X-linked Retinoschisis (XLRS) is an early-onset transretinal dystrophy, often with a prominent macular component, that affects males and generally spares heterozygous females because of X-linked recessive inheritance. It results from loss-of-function RS1 gene mutations on the X-chromosome. XLRS causes bilateral reduced acuities from young age, and on clinical exam and by ocular coherence tomography (OCT) the neurosensory retina shows foveo-macular cystic schisis cavities in the outer plexiform (OPL) and inner nuclear layers (INL). XLRS manifests between infancy and school-age with variable phenotypic presentation and without reliable genotype-phenotype correlations. INL disorganization disrupts synaptic signal transmission from photoreceptors to ON-bipolar cells, and this reduces the electroretinogram (ERG) bipolar b-wave disproportionately to photoreceptor a-wave changes. RS1 gene expression is localized mainly to photoreceptors and INL bipolar neurons, and RS1 protein is thought to play a critical cell adhesion role during normal retinal development and later for maintenance of retinal structure. Several independent XLRS mouse models with mutant RS1 were created that recapitulate features of human XLRS disease, with OPL-INL schisis cavities, early onset and variable phenotype across mutant models, and reduced ERG b-wave to a-wave amplitude ratio. The faithful phenotype of the XLRS mouse has assisted in delineating the disease pathophysiology. Delivery to XLRS mouse retina of an AAV8-RS1 construct under control of the RS1 promoter restores the retinal structure and synaptic function (with increase of b-wave amplitude). It also ameliorates the schisis-induced inflammatory microglia phenotype toward a state of immune quiescence. The results imply that XLRS gene therapy could yield therapeutic benefit to preserve morphological and functional retina particularly when intervention is conducted at earlier ages before retinal degeneration becomes irreversible. A phase I/IIa single-center, open-label, three-dose-escalation clinical trial reported a suitable safety and tolerability profile of intravitreally administered AAV8-RS1 gene replacement therapy for XLRS participants. Dose-related ocular inflammation occurred after dosing, but this resolved with topical and oral corticosteroids. Systemic antibodies against AAV8 increased in dose-dependent fashion, but no antibodies were observed against the RS1 protein. Retinal cavities closed transiently in one participant. Technological innovations in methods of gene delivery and strategies to further reduce immune responses are expected to enhance the therapeutic efficacy of the vector and ultimate success of a gene therapy approach.

MANAGEMENT OF LARGE IDIOPATHIC MACULAR HOLE WITH PARS PLANA VITRECTOMY AND MODIFIED MINIMAL ILM PEELING WITH SUPERIOR ILM FLAP

Introduction: Idiopathic macular hole is an anatomic discontinuity of the neurosensory retina in the center of the macula or fovea resulted from tractional forces on the foveola at the vitreoretinal interface not associated with other causes. Diagnosis and management of this condition requires expertise, skills, and specialized examination to detect changes in the retina which is important for deciding the appropriate management.&#x0D; Case Report: We report a case of 66-year-old man with idiopathic macular hole (IMH) in the right eye with initial best corrected visual acuity (BCVA) 20/1200. Fundus examination and optical coherence tomography (OCT) confirmed the presence of large full thickness macular hole with mean linear diameter 673 µm and posterior hyaloid still attached to the optic nerve. The patient was managed with pars plana vitrectomy (PPV) surgery using modified minimal internal limiting membrane (ILM) peeling with superior ILM flap and SF6 gas tamponade. Two weeks after surgery OCT showed closure of the macular hole. BCVA at two and four weeks after surgery improved to 20/240 and 20/200 respectively.&#x0D; Discussion: PPV with ILM peeling is one of the standardized procedures in IMH surgery. Failure of the vitrectomy surgery to close the macular hole or late reopening of initially successfully closed holes may occur without removal of the ILM due to ILM role as a scaffold for cellular proliferation or attachment of contractile tissue that may cause persistent vitreomacular traction. Variations of ILM peeling such as inverted ILM peeling has been used to improve closure rate for large IMH and has showed favorable results both anatomically and functionally. Nowadays, to avoid or minimize the damage of retinal microstructure by ILM peeling, some surgeons introduced new techniques aiming to preserve the ILM for IMH. Minimal ILM peeling with superior ILM flap technique in this case was done to obtain MH closure with less microstructural retinal abnormalities and better visual outcomes.&#x0D; Conclusion The management of large IMH with PPV and modified minimal ILM peeling with superior ILM flap in this case showed good results in terms of anatomic and functional outcomes.

Simple Code Implementation for Deep Learning-Based Segmentation to Evaluate Central Serous Chorioretinopathy in Fundus Photography.

PurposeCentral serous chorioretinopathy (CSC) is a retinal disease that frequently shows resolution and recurrence with serous detachment of the neurosensory retina. Here, we present a deep learning analysis of subretinal fluid (SRF) lesion segmentation in fundus photographs to evaluate CSC.MethodsWe collected 194 fundus photographs of SRF lesions from the patients with CSC. Three graders manually annotated of the entire SRF area in the retinal images. The dataset was randomly separated into training (90%) and validation (10%) datasets. We used the U-Net segmentation model based on conditional generative adversarial networks (pix2pix) to detect the SRF lesions. The algorithms were trained and validated using Google Colaboratory. Researchers did not need prior knowledge of coding skills or computing resources to implement this code.ResultsThe validation results showed that the Jaccard index and Dice coefficient scores were 0.619 and 0.763, respectively. In most cases, the segmentation results overlapped with most of the reference areas in the annotated images. However, cases with exceptional SRFs were not accurate in terms of prediction. Using Colaboratory, the proposed segmentation task ran easily in a web-based environment without setup or personal computing resources.ConclusionsThe results suggest that the deep learning model based on U-Net from the pix2pix algorithm is suitable for the automatic segmentation of SRF lesions to evaluate CSC.Translational RelevanceOur code implementation has the potential to facilitate ophthalmology research; in particular, deep learning–based segmentation can assist in the development of pathological lesion detection solutions.

An Adenocarcinoma Associated with Bilateral, Diffuse, Uveal Melanocytic Proliferation

Purpose: We report bilateral, diffuse, uveal melanocytic proliferation caused by a stomach adenocarcinoma.Case summary: A 78-year-old male complained of visual impairment 3 months in duration. He had diabetes and had undergone cataract surgery on both eyes 4 years prior. His best-corrected visual acuity was counting fingers in the right eye and 20/160 in the left eye. Both intraocular pressures were normal. The anterior segments yielded no specific findings. The maculae exhibited multiple, round, patchy, pigmented or depigmented lesions with exudative retinal detachment. Fluorescein angiography revealed multiple hyperfluorescent lesions. Optical coherence tomography revealed that the hyper-reflective exudates lay between the neurosensory retina and the retinal pigment epithelium. We diagnosed bilateral, diffuse, uveal melanocytic proliferation and performed a systemic evaluation. Computed tomography revealed several mass lesions in the lung, stomach, and lymph nodes; these appeared to be malignant. An esophagogastroduodenoscopic biopsy confirmed that the lesions were adenocarcinomas.Conclusions: A bilateral, diffuse, uveal melanocytic proliferation induced by a primary malignant tumor exhibited multiple, pigmented subretinal exudates associated with exudative macular retinal detachment. In patients with such findings, it is necessary to evaluate the malignant tumor status of remote organs.

Central serous chorioretinopathy: Treatment.

Central serous chorioretinopathy (CSC) is a pachychoroid spectrum disease characterized by serous detachment of the neurosensory retina with subretinal fluid in young and middle-aged adults. The pathogenesis of CSC is not yet fully understood. However, it is considered a multifactorial disease that is strongly associated with choroidal dysfunction or vascular engorgement. Although there is no consensus on the treatment of CSC, photodynamic therapy has been effectively used to manage serous retinal detachment (SRD) in CSC. Moreover, micropulse diode laser photocoagulation and focal laser treatment have also been used. Recently, oral medications, including mineralocorticoid receptor antagonists, have been proposed for the management of CSC. Multimodal imaging plays a significant role in the diagnosis and treatment of CSC. Optical coherence tomography angiography (OCTA) has the advantage of detecting vascular flow in the retina and choroid layer, allowing for a better understanding of the pathology, severity, prognosis, and chronicity of CSC. In addition, early detection of choroidal neovascularization in CSC is possible using OCTA. This review article aims to provide a comprehensive and updated understanding of CSC, focusing on treatment.

Narrative review of risuteganib for the treatment of dry age-related macular degeneration (AMD)

: Age-related macular degeneration (AMD) is a leading cause of blindness worldwide. AMD most commonly affects older individuals and is characterized by irreversible degeneration of the retinal pigment epithelium and neurosensory retina. Currently, there are limited treatment options for dry AMD outside of lifestyle modification and nutrient supplementation. Risuteganib [Luminate (ALG-1001), Allegro Ophthalmics, CA, USA] is an intravitreally administered inhibitor of integrin heterodimers αVβ3, αVβ5, α5β1, and αMβ2. It is currently undergoing clinical trials for the treatment of dry AMD and diabetic macular edema (DME). Preclinical studies have shown that risuteganib has an effect on the pathways for angiogenesis, inflammation, and vascular permeability. Ongoing clinical trials have had promising results showing improvements in patient best corrected visual acuity (BCVA) and reduced central macular thickness measured by optical coherence tomography (OCT). There is a pressing need for treatments for dry AMD and while risuteganib appears to have a potential benefit for patients, more data are needed before one can truly evaluate its efficacy. This narrative review provides a concise summary of the most up to date data regarding the proposed mechanism of action of risuteganib in the treatment of nonexudative AMD and DME as well as the results from recent phase 1 and phase 2 clinical trials.

Retina mirrors brain pathology and response to GA immunotherapy in advanced stage AD-model mice.

Characteristic signs of Alzheimer's disease (AD) are increasingly reported in the neurosensory retina of human patients and animal models, however examination of the retino-cerebral relationship, especially at late disease stages and in response to therapy, is scarce. Transgenic models of AD (APPSWE /PS1∆E9 ; ADtg mice) treated with glatiramer acetate (GA) immunomodulation showed disease alleviation in pre- and early-symptomatic disease stages. Here, we explored the link between retinal and cerebral AD-related biomarkers, including response to GA immunization, in cohorts of old, advanced-stage ADtg mice. These mice were aged to become more clinically relevant to AD. To determine the extent of amyloid β-protein (Aβ) burden in retinal and brain tissues from treated and untreated ADtg mice, we developed a new protocol for extracting, unfolding and quantifying Aβ levels utilizing a Meso Scale Discovery biochemical assay, which recognizes human and mouse Aβ1-42 , Aβ1-40 , and Aβ1-38 proteins. Homogenates from these tissues were additionally analyzed by mass spectrometry for detailed global protein levels. Immunohistochemical staining for Aβ plaques, inflammation, infiltrating myeloid cells, and synapses were conducted on brain sections to reveal cerebral effects of GA immunotherapy. Levels of synaptotoxic Aβ1-42 , angiopathic Aβ1-40 , non-amyloidogenic Aβ1-38 , and Aβ42 /Aβ40 ratios tightly correlated between paired retinas derived from oculus sinister (OS) and oculus dexter (OD) eyes, and between left and right brain hemispheres. Brains and retinas displayed significant, one-side dominant lateralization of Aβ burden. Importantly, OS and OD retinal Aβ levels correlated with their cerebral counterparts, in advanced disease stage and following GA immunotherapy, with stronger contralateral correlations. Moreover, immunomodulation in old ADtg mice provoked reductions in vascular and parenchymal Aβ deposits in the brain, especially of large, dense-core plaque subtypes, and alleviation of microgliosis and astrocytosis. Immunization further enhanced cerebral recruitment of peripheral myeloid cells and synaptic preservation. Global proteome profiling by mass spectrometry revealed novel molecular parallels in retino-cerebral AD-related pathology and response to GA immunization, including restoration of homeostatic astrocytic glutamine synthetase expression. Overall, our results support the sustainability of immunomodulation in provoking CNS repair, even in advanced-stage AD-model mice, while revealing similarities in retino-cerebral responses to therapy, providing incentives to explore retinal AD biomarkers.