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Retinopathy of prematurity (ROP) is a neovascular retinal disorder that occurs in infants born prematurely. Nowadays, ROP constitutes a leading cause of childhood blindness worldwide and for decades the standard of care has involved peripheral retinal ablation. However, this type of treatment requires the use of specialized equipment by well-trained physicians, has been associated with poor structural and visual outcomes in some preterm infants, and despite its adequate application, some cases of ROP may continue to progress. Therefore, the need for simpler and more efficient strategies made anti-vascular endothelial growth factor (anti-VEGF) medications an appealing option for treatment. Recently, the use of anti-VEGF agents for ROP has increased worldwide; nevertheless, this practice remains off-label, and there is a lack of information regarding its safety profile and the possibility of unfavorable long-term outcomes causes the utmost concern. This review updates the recent evidence regarding the systemic and ocular safety of anti-VEGF treatment for ROP.

Choroby siatkówki stanowią dużą grupę schorzeń narządu wzroku. W leczeniu wielu z nich od lat z powodzeniem stosowana jest laseroterapia. Mimo prób wprowadzania do terapii innych metod leczniczych nadal pozostaje jedną z głównych opcji terapeutycznych. W pracy przedstawiono przegląd piśmiennictwa dotyczący zastosowania laseroterapii w chorobach siatkówki, z uwzględnieniem nowych rodzajów i sposobów laseroterapii. Pracę podzielono na trzy części. W części pierwszej, publikowanej w niniejszym numerze przedstawiono metodykę i rodzaje zabiegów laserowych. W kolejnych numerach pisma ukażą się: część druga, zawierająca przegląd piśmiennictwa dotyczący laseroterapii w retinopatii cukrzycowej, cukrzycowym obrzęku plamki oraz chorobach naczyniowych siatkówki (nr 3), i trzecia, ukazująca przegląd piśmiennictwa dotyczący laseroterapii w przedarciach oraz chorobach zwyrodnieniowych siatkówki, retinopatii wcześniaków, zwyrodnieniu plamki związanym z wiekiem oraz innych chorobach siatkówki (nr 4).

Background: The analysis of retinal images can help to detect retinal abnormalities that are caused by cardiovascular and retinal disorders. Objective: In this paper, we propose methods based on texture features for mining and analyzing information from retinal images. Methods: The recognition of the retinal mask region is a prerequisite for retinal image processing. However, there is no way to automatically recognize the retinal region. By quantifying and analyzing texture features, a method is proposed to automatically identify the retinal region. The boundary of the circular retinal region is detected based on the image texture contrast feature, followed by the filling of the closed circular area, and then the detected circular retinal mask region can be obtained. Results: The experimental results show that the method based on the image contrast feature can be used to detect the retinal region automatically. The average accuracy of retinal mask region detection of images from the Digital Retinal Images for Vessel Extraction (DRIVE) database was 99.34%. Conclusion: This is the first time these texture features of retinal images are analyzed, and texture features are used to recognize the circular retinal region automatically.

Inherited retinal disorders (IRDs) are the most common cause of certifiable blindness in working-age adults in the UK. There are currently no treatments for the majority of patients, resulting in c...

In vivo fundus imaging offers non-invasive access to neuron structures and biochemical processes in the retina. However, optical aberrations of the eye degrade the imaging resolution and prevent visualization of subcellular retinal structures. We developed an adaptive optics two-photon excitation fluorescence microscopy (AO-TPEFM) system to correct ocular aberrations based on a nonlinear fluorescent guide star and achieved subcellular resolution for in vivo fluorescence imaging of the mouse retina. With accurate wavefront sensing and rapid aberration correction, AO-TPEFM permits structural and functional imaging of the mouse retina with submicron resolution. Specifically, simultaneous functional calcium imaging of neuronal somas and dendrites was demonstrated. Moreover, the time-lapse morphological alteration and dynamics of microglia were characterized in a mouse model of retinal disorder. In addition, precise laser axotomy was achieved, and degeneration of retinal nerve fibres was studied. This high-resolution AO-TPEFM is a promising tool for non-invasive retinal imaging and can facilitate the understanding of a variety of eye diseases as well as neurodegenerative disorders in the central nervous system., Adaptive-Optics Fluorescence Microscopy: Seeing clearly into eyes An advance in Two-Photon Excitation Fluorescence Microscopy (TPEFM) allows greatly improved subcellular imaging of the retina, promising better understanding of the eye and the central nervous system in health and disease. Researchers led by Jianan Y. Qu at Hong Kong University of Science and Technology used adaptive optics techniques to correct the optical aberrations that have limited application of TPEFM in living eyes. They demonstrated their innovation using fluorescent detector molecules to image the activity of calcium ions in mouse retinal neurons. They also monitored subcellular structures in microglial cells, and guided laser light to cut the axons that transmit nerve signals. This technology could help investigate the development of neurodegenerative diseases, since the eye offers a window into nerves of the central nervous system that link the eye with the brain.

Genetic heterogeneity leading to retinal disorders impairs biological processes by causing, for example, severe disorder of signal transduction in photoreceptor outer segments. A normal balance of ...

Acute zonal occult outer retinopathy (AZOOR) is an outer retinal disorder characterized by the acute loss of visual functions. Herein, we report a case of AZOOR presenting features mimicking optic neuritis. A 17-year-old healthy male reported fogginess in the right eye for 2 weeks. His best-corrected visual acuity was 20/20 in both eyes. Results of a color vision test and pupillary reaction were unremarkable. Funduscopic examination revealed a subtle hyperemic disc surrounded by hyperpigmentation in the right eye. Visual field examination confirmed an enlarged blind spot in the affected eye. Fundus autofluorescence imaging revealed zonal hyperautofluorescence around the optic disc. Fluorescein angiography showed optic disc staining and a window defect in the retinal pigment epithelium. Optical coherence tomography demonstrated loss of the ellipsoid line at the corresponding hyperautofluorescent region. All these characteristics indicated a diagnosis of AZOOR. However, the prolonged P100 wave observed through visual-evoked potential examination, hyperintensity T2 signal at the retrobulbar optic nerve through magnetic resonance imaging, and mild hyperemic optic disc along with optic disc staining through fluorescein angiography resemble the characteristics of optic neuritis. Because the clinical features of AZOOR are similar to those of optic neuritis, ophthalmologists should be able to differentiate between these two diseases to achieve a timely and correct diagnosis.

Objective: To investigate trends in terms of number and cost of intravitreal injection, photocoagulation and panphotocoagulation procedures performed by the Brazilian Public Health System, from 2010 to 2019. Methods: The Brazilian Public Health System Database was used as the primary source of data. Intravitreal injection, photocoagulation and panphotocoagulation procedures performed from 2010 to 2019 were investigated. Procedure prevalence and cost trends were analyzed according to year and region. Annual trends were examined using generalized linear models, with a significance level of 5% (p=0.05). Results: There was a significant increase in the prevalence of intravitreal injections (1,088%), panphotocoagulation (51%) and photocoagulation (37%) procedures from 2010 to 2019. Intravitreal injections accounted for the most significant increase. However, costs were not significantly readjusted over the years. Conclusion: Over a 10-year period, there was a significant increase in the number of procedures associated with retinal disorders. Procedure costs saw little readjustments over time. In spite of limitations, inaccuracies and lack of details, the Brazilian Public Health System Database is the primary source of data for the Public Health System related research in Brazil, and can contribute with information on ocular health and costs of ophthalmic procedures. RESUMO Objetivo: Investigar as tendências dos números e dos custos dos procedimentos de injeção intravítrea, fotocoagulação e panfotocoagulação realizados pelo Sistema Único de Saúde brasileiro, no período de 2010 a 2019. Métodos: Foram extraídos dados do Departamento de Informática do Sistema Único de Saúde acerca dos atendimentos associados aos procedimentos de injeção intravítrea, fotocoagulação e panfotocoagulação, realizados de 2010 a 2019. A prevalência de procedimentos e os custos foram analisados por ano e por região de atendimento. As tendências ao longo dos anos foram avaliadas por meio de modelos lineares generalizados. Valores de p=0,05 foram considerados estatisticamente significantes. Resultados: Em relação aos procedimentos específicos, houve aumento nas frequências de injeção intravítrea (1.088%), panfotocoagulação (51%) e fotocoagulação (37%), no comparativo de 2010 a 2019. A injeção intravítrea foi o procedimento que apresentou maior crescimento ao longo dos anos, porém não houve reajuste de custo significativo durante o período estudado. Conclusão: Ao longo de 10 anos, houve aumento significativo do número de atendimentos associados aos tratamentos de distúrbios da retina. Os custos relacionados aos procedimentos mostraram pouco reajuste ao longo dos anos. Embora o Departamento de Informática do Sistema Único de Saúde apresente algumas limitações, como imprecisões e falta de detalhamento em alguns procedimentos, esta é a ferramenta de dados disponível no Brasil para o acesso a pesquisa relacionada ao Sistema Único de Saúde e pode contribuir com informações da saúde ocular e os custos dos procedimentos.

Retinopathy of prematurity (ROP) is a vasoproliferative retinal disorder. Although its clinical presentation, classification, and treatment has been known in detail for several years, ROP remains as one of the leading causes of treatable childhood blindness worldwide, mainly in middle-income countries. Understanding ROPs epidemiology, pathophysiology, and risk factors enables better timely screening, monitoring, and treatment. ROP is a complex disease, which needs a multidisciplinary team to ensure appropriate care and management.

Automatic detection of retinal disorders is gaining considerable attention with the emergence of deep learning. Ophthalmologists primarily use color fundus photographs to examine the human retina and diagnose the abnormalities. As there is a surge in the number of visual impairments, an AI-enabled retina screening system can expedite the retina examination process. Existing works in this direction are primarily focused on either segmentation or classification. Furthermore, the majority of the works are implemented using preprocessed good quality fundus images. In reality, however, the quality of color fundus images is degraded due to the illumination inhomogeneity and low contrast issues. Thus, there is a need to develop an end-to-end fundus image analysing system. Steering in this direction, the proposed work attempts to analyze the performance of semi-supervised Generative Adversarial Networks (GANs) for the classification of retinal fundus images into multiple categories. Besides, the nonlocal retinex framework is applied to enhance the quality of fundus images without over-smoothing the edges. The large data set of raw fundus acquired from multiple Eye hospitals and released in public domain is used to implement the proposed work. The results obtained are compared with the transfer learning method, and an average accuracy of 87% is obtained. It suggests that the semi-supervised GANs can be potentially used to classify heterogeneous retinal disorders.

The eye is considered an effective target for genetic therapy, as it has a privileged immune status, it is easily accessed for medication delivery and it is affected by a number of inherited disorders. In particular, the retina is considered for gene therapy due to the fact that it can be visualized with ease, it does not have lymphatic vessels, nor a direct blood network for the outer layers and its cells do not divide after birth, and thus transgene expression is not affected. As gene therapy is currently on a continuously progressive development trend, this emerging field of gene manipulation techniques has yielded promising results. This involves the development of treatments for a number of debilitating and blinding diseases, which were to date considered intractable. However, numerous unanswered questions remain as regards the long-term efficacy and safety profile of these treatments. The present review article discusses the current research status regarding genetic manipulation techniques aimed at addressing visual impairment related to retinal disorders, both inherited and degenerative.

Laser photocoagulation is a safe method for the treatment of retinal disorders. We present a case of a 21-year-old woman with high myopia, retinal detachment in the right eye, and bilateral lattice degeneration. She underwent surgical repair in the right eye followed by bilateral retinal laser therapy. During laser photocoagulation of the left eye, she experienced a generalized tonic-clonic seizure for the first time in her life. She had a positive family history of epilepsy. Neurological examination and brain magnetic resonance imaging findings were normal, but an electroencephalogram revealed epileptogenic discharges, more frequent during photostimulation. She avoided flickering lights during the 2-year follow-up, without seizure recurrence. Approximately 5% of patients with epilepsy have photosensitive epilepsy, of whom a considerable proportion will experience seizures only during exposition to flashing lights. Laser photocoagulation was already successfully employed in an animal model of photosensitive epilepsy. Personal or family history of photosensitivity warrants a neurological consultation before retinal treatment with laser therapy. RESUMO Fotocoagulação a laser é método seguro para tratamento de retinopatias. Apresentamos o caso de uma mulher de 21 anos com alta miopia e degeneração lattice bilateral que sofreu descolamento de retina no olho direito e foi submetida a tratamento cirúrgico e ulterior laserterapia. Durante a fotocoagulação no olho esquerdo, ela teve uma convulsão tônico-clônica generalizada, a primeira em sua vida. Havia história familiar de epilepsia. O exame neurológico e a ressonância magnética de en céfalo foram normais, mas o electroencefalograma revelou descargas epileptogênicas, mais frequentes durante a fotoesti mulação. Ela evitou luzes piscantes durante os 2 anos subsequentes, sem recorrência de convulsões. Cerca de 5% dos pacientes com epilepsia têm fotossensibilidade. Proporção considerável deles terá convulsões somente durante exposição à luz piscante. Fotocoagulação a laser já foi empregada como modelo animal de sucesso para epilepsia fotossensível. Presença de fotossensibilidade na história pessoal ou familiar deve merecer avaliação neurológica antes do tratamento retiniano.

The RLBP1 gene encodes the 36 kDa cellular retinaldehyde binding protein, CRALBP, a soluble retinoid carrier, in the visual cycle of the eyes. Mutations in RLBP1 are associated with recessively inherited clinical phenotypes, including Bothnia dystrophy, retinitis pigmentosa, retinitis punctata albescens, fundus albipunctatus, and Newfoundland rod-cone dystrophy. However, the etiology of these retinal disorders is not well understood. Here, we generated homologous zebrafish models to bridge this knowledge gap. Duplication of the rlbp1 gene in zebrafish and cell-specific expression of the paralogs rlbp1a in the retinal pigment epithelium and rlbp1b in Müller glial cells allowed us to create intrinsically cell type-specific knockout fish lines. Using rlbp1a and rlbp1b single and double mutants, we investigated the pathological effects on visual function. Our analyses revealed that rlbp1a was essential for cone photoreceptor function and chromophore metabolism in the fish eyes. rlbp1a mutant fish displayed reduced chromophore levels and attenuated cone photoreceptor responses to light stimuli. They accumulated 11-cis and all-trans-retinyl esters which displayed as enlarged lipid droplets in the RPE reminiscent of the subretinal yellow-white lesions in patients with RLBP1 mutations. During aging, these fish developed retinal thinning and cone and rod photoreceptor dystrophy. In contrast, rlbp1b mutants did not display impaired vision. The double mutant essentially replicated the phenotype of the rlbp1a single mutant. Together, our study showed that the rlbp1a zebrafish mutant recapitulated many features of human blinding diseases caused by RLBP1 mutations and provided novel insights into the pathways for chromophore regeneration of cone photoreceptors.Graphical Abstract

Introduction Pregnancy may be associated to unique retinal disorders and is associated to worsening of retinal disease that also occurs in non-pregnant females. We report a case of chorioretinopathy caused by pre-eclampsia associated to HELLP (Hemolysis-Elevated-Liver enzymes and Low Platelet count) syndrome. Methods Multimodal Imaging features of HELLP syndrome-related hypertensive chorioretinopathy including retinography, Spectral Domain-Optical Coherence Tomography (SD-OCT), Fluorescein angiography (FA), Indocyanine-green angiography (ICG) along with OCT-angiography (OCTA) are presented and discussed. Results Multimodal imaging and OCTA show both retinal and choroidal involvement by HELLP syndrome, resolved after hypertension treatment. Conclusions Multimodal imaging is useful to study HELLP syndrome-related hypertensive chorioretinopathy. Moreover, OCTA is a new technology able to study and follow the circulatory status of the choriocapillaris during the disease.

X-linked retinitis pigmentosa (XLRP), a rare form of retinitis pigmentosa (RP), is predominantly caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. Affected males often present with severe phenotypes and early disease onset. In contrast, female carriers are usually asymptomatic or show stationary phenotypes. Herein, we reported an 8-year-old female carrier, a daughter of a confirmed RP father with RPGR mutation, with an early onset of progressive cone-rod pattern retinal dystrophy. Additionally, the carrier experienced visual snow-like symptom as long as she recalled. Ophthalmological examination showed the reduction of visual acuity and attenuation of photoreceptor functions since the age of 5 years. Further analysis revealed a heterozygous pathogenic variant of the RPGR gene and a random X-inactivation pattern. Although she harboured an identical RPGR variant as the father, there were phenotypic intrafamilial variations. The information on the variety of genotypic and phenotypic presentations in XLRP carriers is essential for further diagnosis, management, and monitoring of these cases, including the design of future gene therapy trials.

Retinopathy of prematurity is defined as retinal abnormalities that occur during development as a consequence of disturbed oxygen conditions and nutrient supply after preterm birth. Both neuronal maturation and retinal vascularization are impaired, leading to the compensatory but uncontrolled retinal neovessel growth. Current therapeutic interventions target the hypoxia-induced neovessels but negatively impact retinal neurons and normal vessels. Emerging evidence suggests that metabolic disturbance is a significant and underexplored risk factor in the disease pathogenesis. Hyperglycemia and dyslipidemia correlate with the retinal neurovascular dysfunction in infants born prematurely. Nutritional and hormonal supplementation relieve metabolic stress and improve retinal maturation. Here we focus on the mechanisms through which metabolism is involved in preterm-birth-related retinal disorder from clinical and experimental investigations. We will review and discuss potential therapeutic targets through the restoration of metabolic responses to prevent disease development and progression.

Purpose The occurrence of relative afferent pupillary defect (RAPD) secondary to optic nerve diseases and widespread retinal disorders is well established. However, only very few reports of RAPD in macular disorders exist in the literature. In this study, we used automated pupillometer to evaluate RAPD in eyes with macular lesions. Methods It was a prospective cross-sectional study. A total of 82 patients with choroidal neovascular membrane (CNVM) - 65 unilateral and 17 bilateral macular lesions - were enrolled. RAPD was assessed with an automated pupillometer and macular lesions evaluated with optical coherence tomography (OCT). The length of the ellipsoid zone disruption was measured as the longest length of lesion on the horizontal raster scans and the area of macular lesion was measured manually, mapping the affected area of ellipsoid zone on the enface images. Results : RAPD scores showed good correlation with the intereye difference in length of maximum ellipsoid zone disruption (r-value = 0.84, P value

The terms “congenital grouped albinotic spots” (CGAS) and “polar bear tracks” refer to a rare, benign retinal disorder of unknown etiology characterized by multiple, predominantly unilateral, variably sized, well-circumscribed, flat white retinal spots organized in groups. To date, very few cases of CGAS have been reported. The authors describe a case of CGAS thoroughly characterized by multimodal imaging over an 8-year follow-up, aiming to provide new insights on the pathophysiology of this entity. This is the first report where a long follow-up combined with up-to-date imaging technology is used to characterize CGAS. [ Ophthalmic Surg Lasers Imaging Retina . 2020;51:236–238.]

Peroxisome proliferator-activated receptor alpha (PPARα) is expressed in retinal Müller cells, endothelial cells, and in retinal pigment epithelium, and agonism of PPARα with genetic or pharmacological tools ameliorates inflammation, vascular leakage, neurodegeneration, and neovascularization associated with retinal diseases in animal models. As such, PPARα is a promising drug target for diabetic retinopathy and age-related macular degeneration. Herein, we report proof-of-concept in vivo efficacy in an STZ-induced vascular leakage model (rat) and preliminary pharmacokinetic assessment of a first-generation lead 4a (A91). Additionally, we present the design, synthesis, and evaluation of second-generation analogs, which led to the discovery of 4u and related compounds that reach cellular potencies 2,700-fold selectivity for PPARα over other PPAR isoforms. These studies identify a pipeline of candidates positioned for detailed PK/PD and pre-clinical evaluation.

Recent advances in pharmacological agents have led to successful treatment of a variety of retinal diseases such as neovascular age-related macular degeneration (AMD), diabetic macular oedema (DMO), and retinal vascular occlusions (RVO). These treatments often require repeated drug injections for an extended period of time. To reduce these repeated treatment burdens, minimally invasive drug delivery systems are needed. An ideal therapy should maintain effective levels of drug for the intended duration of treatment following a single application, recognising that a significant number of months of therapy may be required. There are numerous approaches under investigation to improve treatment options. This review will highlight the advantages and limitations of selected drug delivery systems of novel biomaterial implants and depots. The main emphasis will be placed on less invasive, longer acting, sustained release formulations for the treatment of retinal disorders.摘要: 近年来, 药理学方面的进步改善了多种视网膜疾病的预后, 例如新生血管性年龄相关性黄斑变性 (AMD), 糖尿病性黄斑水肿 (DMO) 和视网膜血管阻塞 (RVO)。此类疾病的治疗通常需要长期反复注射给药, 为了减少重复性治疗的负担, 尽可能使用无创的药物传输系统。考虑到可能需要数月的治疗周期, 理想的治疗方式是在单次给药后较长时间内能保持有效的药物浓度。目前多种药物正在研发之中以改善药物治疗方案。本篇综述概括了几种特定的新型生物材料植入物和缓释库给药途径的优势和局限性。重点介绍了治疗视网膜疾病的侵入性小, 作用时间长, 持续性释放的几种制剂。.

High rated and active research in Ophthalmic field has paved the way for the detection of several retinal disorders which helps the ophthalmologist, in scheduling and executing timely treatment. Th...

Purpose Multifocal intraocular lenses (MIOLs) are often discouraged in patients with or at risk of retinal disorders (including diabetic retinopathy, age-related macular degeneration, and epiretinal membranes), as MIOLs are believed to reduce contrast sensitivity (CS). Concerns with MIOLs have also been raised in individuals with visual field defects, fixation instability or eccentric preferred retinal locations. The aim of this study is to review the influence of MIOL on quality of vision in patients with retinal diseases. Methods We reviewed the PubMed and Web of Science databases to identify relevant studies using the following keywords: multifocal intraocular lens, cataract surgery, cataract extraction, lens exchange, diabetic retinopathy, age-related macular degeneration, and contrast sensitivity. Results Studies evaluating CS in MIOLs present conflicting results: MIOLs either did not influence CS or resulted in worse performance under low-illuminance conditions and higher spatial frequencies when compared to monofocal IOLs. Nevertheless, MIOLs preserved CS levels within the age-matched normal range. Two studies reported that patients with concurrent retinal diseases receiving a MIOL, both unilaterally and bilaterally, reported a significant improvement in visual-related outcomes. Individuals with a monofocal IOL in one eye and a MIOL in the fellow eye reported greater subjective satisfaction with the MIOL. Conclusion We were unable to find evidence suggesting that patients with retinal diseases should be advised against MIOLs. Nevertheless, more research is needed to address the aforementioned concerns and to optimize the use of MIOLs in eyes with retinal disease.

Using stem and progenitor cells to treat retinal disorders holds great promise. Using defined culture conditions to maintain the desires phenotype is of utmost clinical importance. We cultured human retinal progenitor cells (hRPCs) in different conditions: such as normoxia (20% oxygen), and hypoxia (5% oxygen) with and without knock-out serum replacement (KOSR) to evaluate its effect on these cells. KOSR is known nutrient supplement often used to replace bovine serum for culturing embryonic or pluripotent stem cells, especially those destined for clinical applications. The purpose of this study was to identify the impact of different environmental and chemical cues to determine if this alters the fate of these cells. Our results indicate that cells cultured with or without KOSR do not show significant differences in viability, but that the oxygen tension can significantly change their viability (higher in hypoxia than normoxia). However, cells with KOSR in hypoxia condition expressed significantly higher stemness markers such as C-myc and Oct4 (31.20% and 13.44% respectively) in comparison to hRPCs cultured in KOSR at normoxia (12.07% and 4.05%). Furthermore, levels of markers for retinal commitment such as rhodopsin were significantly lower in the KOSR supplemented cells in hypoxia culture compared to normoxia. KOSR is known to improve proliferation and maintain stemness of embryonic cells and our experiments suggest that hRPCs maintain their proliferation and stemness characteristics in hypoxia with KOSR supplement. Normoxia, however, results in mature cell marker expression, suggesting a profound effect of oxygen tension on these cells.

Purpose Optical coherence tomography angiography (OCTA) is used to assess vascular abnormality in advanced stage vitelliform macular dystrophy (VMD2). Methods Multimodal imaging including spectral domain (SD) OCT, autofluorescence (AF), fluorescein (FA) and indocyanine green angiography (ICGA) as well as optical coherence tomography angiography were performed. Patients Two eyes in one young patient with diagnosed vitelliform macular dystrophy were investigated for progressive visual dysfunction. Results Optical coherence tomography angiography identified neovascular formation within the outer retina and the choriocapillaris respectively while all other imaging methods were inconclusive. Conclusion Optical coherence tomography angiography was superior to conventional angiography in the detection of choroidal neovascularization (CNV) in advanced retinal disorders like vitelliform macular dystrophy.

Age-related macular degeneration represents the main retinal disorder leading to irreversible blindness in people over the age of 50 in the Western World. Here we describe a case report, which suggest that specific nutraceutical compounds may exert beneficial effects on the progression of dry age-related macular degeneration (AMD), an eye disease with no approved treatment or cure. Specific antioxidants, such as lutein, resveratrol and Vaccinium Myrtillus, which are known to reduce the risk of developing AMD, when co-administered alone, were supplemented to diet of an informed patient suffering from dry AMD. The case report indicates an improvement of visual acuity and a long lasting decrease in druse volume and number. The concomitant intake of lutein, resveratrol and Vaccinium Myrtillus when administered for six months produced a marked decrease in the drusen observed at OCT at the 6-month follow-up. At this time interval, the patient experienced a noticeable improvement in visual acuity, a decrease in eye strain, more color contrast, higher visual definition. The case report indicates the potential benefit for a non-invasive treatment with improved quality of vision in dry AMD. A larger population followed over a long-term period is warranted. The support of nutraceuticals could therefore offer a new non-invasive, adverse effect-free which may restore the pathology affecting the cross talk between choroid and retinal cells. The results of this case report are discussed within the frame of molecular mechanisms synergizing site-specifically at the anatomical border between the outer retina and inner choroid.

Aging causes the progressive degeneration of retinal cells leading to the eventual loss of vision. The hormone prolactin (PRL) is a neurotrophic factor able to compensate for photoreceptor cell death and electroretinogram deficits induced by light retinal damage. Here, we used adult 4-month old and aged 20-month old pigmented mice, null or not for the PRL receptor to explore whether PRL provides trophic support against age-related retinal dysfunction. Retinal functionality, apoptosis, glia activation, and neurotrophin expression were assessed by electroretinogram, TUNEL, glial fibrillary acidic protein and ionized calcium binding adaptor molecule 1 immunohistochemistry, and real-time PCR, respectively. Lack of PRL signaling in aged mice, but not in adult mice, correlated with photosensitive retinal dysfunction, increased photoreceptor apoptosis, differential expression of proapoptotic mediators, and microglia activation. We conclude that PRL is required for maintaining retinal functionality in both female and male mice during aging and has potential therapeutic value against age-related retinal disorders.

Introduction Inherited retinal dystrophies are major cause of severe progressive vision loss in children. Early recognition and diagnosis are essential for timely visual rehabilitation during the appropriate stages of the visual development, as well as for genetic diagnosis and possible gene therapy. The aim of this study is to characterize a pattern of the initial visual symptoms, which could help the pediatricians and the primary care providers to suspect an inherited retinal disorder in its early stage. Methods We analyzed the initial clinical symptoms, based on parental report during the first visit to specialist, in 50 children diagnosed with retinal dystrophy confirmed by full-field electroretinography. The analysis included the age of symptoms onset and the type of visual symptoms, both in the total population and in the following diagnostic subgroups: rod-cone dystrophy (n.17), cone-rod dystrophy (n.12), achromatopsia (n.13), congenital stationary night blindness (n.6) and Leber’s congenital amaurosis (n.2). Results The majority of children (80%) had the onset of clinical symptoms before one year of age. The most frequent visual complaints reported by parents were nystagmus (76%), visual loss (28%) and photophobia (8%). Nystagmus was the first symptom reported by parents if the disease onset was before the age of six months, while the onset after the six months of age was more likely associated with the complain of vision loss. Conclusions Low vision and nystagmus observed by parents, particularly in the first year of life, may represent a red flag, prompting an appropriate ophthalmological workup for inherited retinal dystrophy.

Innovative advances in recent years in the study of pathological changes of the posterior segment of the eye including the use of optical coherence tomography which is considered the gold standard for diagnosing vitreoretinal interface pathology, not only significantly expanded the idea of the most prevalent lesions of the structure of posterior eye segment but also discovered absolutely new aspects of their pathology. The review emphasizes the spreading understanding of vitreous body, its age-related changes in the pathology of the posterior eye segment. Two main interrelated processes occurring in the vitreous body - synchysis and syneresis, gradually increasing with age, are considered. Synchysis process begins at the early age and by the age of 70 reaches 50% of the volume of the vitreous body in 70% of the population. Parallelly, syneresis provides strength and plasticity of the entire vitreous volume due to collagen involved in formation of fibrillar frame. An important role in maintaining a stable and viscoelastic structure of the vitreous body, belonging to hyaluronic acid, is discussed, the level of which remains relatively stable at any age due to its constant synthesis. The accumulated data on the structure of age-related and pathological biodegradation of the vitreous body demonstrates inevitable progression of this process leading to age-related posterior vitreous detachment, which is a detachment of the posterior cortical layers of the vitreous body from subjacent retina. Posterior detachment under the influence of age-related changes in the vitreous body has certain stages - from incomplete juxtafoveolar detachment to complete posterior vitreous detachment with clinical retinal changes corresponding to each stage (idiopathic macular holes, lamellar macular tears, macular fibrosis, vitreomacular traction syndrome, myopic foveoschisis). Complete posterior vitreous detachment usually does not cause anatomical retinal disorders and any clinical forms of its diseases, thus, it can be considered as a natural favorable outcome.

The International Society for Clinical Electrophysiology of Vision (ISCEV) standard for full-field electroretinography (ERG) describes a minimum procedure for testing generalized retinal function but encourages more extensive testing. This extended protocol describes a method of assessing the function of the short-wavelength-sensitive cone (S-cone) retinal pathway, using a short-wavelength flash superimposed on a background that saturates the rods and adapts the L/M-cones to elicit a response, known as the S-cone ERG. Stimulus parameters such as the strength and luminance of the flash and background, respectively, and their spectral and temporal characteristics are specified. As a complement to the ISCEV standard, testing the S-cone ERG enables further characterization of light-adapted retinal function and may refine diagnosis of some retinal disorders. Typical applications are described including use in the diagnosis of rod monochromacy and S-cone monochromacy, identification and investigation of cone On-bipolar cell dysfunction and use of the technique to confirm the diagnosis of enhanced S-cone syndrome.

Electrically stimulating the retina of the patients suffering due to extreme retinal disorders such as age related macula degeneration, retinitis pigmentosa is quickly turning into a feasible accomplishment through retinal implants. The objective of this work is to optimise the design, develop and test an organic photovoltaic based Nano Photo Diode Array (NPDA) device for retinal prosthesis application to restoring vision to patients blinded by degenerative retinal diseases. NPDA for subretinal stimulation has been fabricated based on Bulk heterojunction (BHJ) solar cell technology. Each pixel is composed by a graphene alone bottom anode, a semiconducting single wall carbon nanotube (S-SWCNT):C60 blend, and a top cathode in aluminum (Al) of 100 µm or 150 diameter. This NPDA device photovoltaically converts incident light into electric current to stimulate nearby retinal neurons without wired power connections. The fabricated device is able to provide a photo current density of 245 µA/cm 2 and photovoltage of 0.31 V. These results suggest that BHJ cell employed photodiode array used in this work make it better than POLYRETINA and SCNC. The significant improvement in photocurrent density paves the way for scaling up density of NPDA array in implant. Increased number of electrodes will indeed enhance visual acuity to greater extent.

Purpose Chronic oxidative stress is an important mechanism of disease in aging disorders. We do not have a good model to recapitulate AMD and other retinal disorders in which chronic oxidative stress plays an important role. We hypothesized that mice with a combined deficiency in superoxide dismutase 1 (Sod1), DJ-1 (Park-7), and Parkin (Prkn) (triple knock out, TKO) would have an increased level of chronic oxidative stress in the retina, with anatomic and functional consequences just with aging. Methods Eyes of TKO and B6J control mice were (1) monitored with optical coherence tomography (OCT) and electroretinography (ERG) over time, and (2) collected for oxidative marker protein analysis by ELISA or immunohistochemistry and for transmission electron microscopy studies. Results TKO mice developed qualitative disruptions in outer retinal layers in OCT by 3 months, increased accumulation of fundus spots and subretinal microglia by 6 months of age, significant retinal thinning by 9 months, and decreased ERG signal by 12 months. Furthermore, we found increased accumulation of the oxidative marker malondialdehyde (MDA) in the retina and increased basal laminal deposits (BLD) and mitochondria number and size in the retinal pigment epithelium of aging TKO mice. Conclusions TKO mice can serve as a platform to study retinal diseases that involve chronic oxidative stress, including macular degeneration, retinal detachment, and ischemic retinopathies. In order to model each of these diseases, additional disease-specific catalysts or triggers could be superimposed onto the TKO mice. Such studies could provide better insight into disease mechanisms and perhaps lead to new therapeutic approaches.

Objective: Microperimetry (MP) is used to assess visual sensitivity mediated by the central retina. As such, MP performance is a candidate outcome measure for gene therapy trials. Herein, we review MP results in three inherited retinal disorders for which gene therapy trials have been initiated-choroideremia, Stargardt disease, and X-linked juvenile retinoschisis. Each of these disorders typically presents in childhood and each has distinct effects on the central retina. Outcomes and Results: Our review indicates that microperimetry is feasible in each of these conditions. The MP sensitivity maps vary among conditions consistent with known effects of each of the three conditions. There is, however, within each of the three disorders considerable variability in fixation stability and in the pattern of sensitivity loss. Conclusions: Microperimetry is a valuable tool for monitoring functional aspects of central retina in an individual patient, especially in combination with other modalities such as OCT, autofluorescence, and acuity and thus may contribute to evaluating the efficacy of gene treatments. Variability of the MP parameters raises some cautions in application of MP as an outcome measure in treatment trials that may have small sample sizes. Nonetheless, we suspect that MP will continue to have a rightful place in future gene therapy trials.

Laser has many uses in ophthalmology depending on its interaction with the different layers of the eye. Laser photocoagulation techniques are used to manage many retinal disorders such as Diabetic Retinopathy by stopping the progress of the disease and prevent blindness through applying small burns on the retina to prevent the severe bleeding of the retinal blood vessels. This treatment procedure requires photocoagulation of the entire peripheral retina in order to save central vision. However, for each eye, it requires several thousands of laser shots that could be achieved in several hours divided over many treatment sessions. Instead, sending a pattern of laser spots could minimize the time required to photocoagulate the retina, hence, the photocoagulation process could be achieved through less treatment sessions, which is needed due to the increasing number of patient and relative shortage of ophthalmologists worldwide. In this work, a technique for multi-spot laser delivery system that can send a desirable pattern of laser spots to the retina in one shot was experimentally implemented and investigated. The optical setup utilized the application of liquid crystal display as a two dimensional array optical switch allowing laser spots to pass through it according to a predetermined pattern providing promising results as a multi-spot laser system to minimize treatment sessions and human errors.

The incidence and treatment of common eye disorders in Bangladesh are poorly understood. This study aims to provide a comprehensive overview of this clinical challenge to better enable the design of appropriate healthcare strategies. The incidence and treatment of common eye disorders in Bangladesh are poorly understood. This study aims to provide a comprehensive overview of this clinical challenge to better enable the design of appropriate healthcare strategies. Different types of eye disorder data were collected from patients aged 1 to 96 years admitted for eye surgery from March 2016 to October 2016 (N = 2390) at the Bangladesh Eye Hospital in Dhaka, Bangladesh. Patient age distribution and types of treatment received were analysed, and incidence rates calculated. Patients (58% male) underwent a total of 43 different types of eye surgeries. Among the surgeries reported 32.8% were Avastin intravitreal injections, 25.5% were Phaco with IOL, 14.6% were retinal laser therapies, 7.5% were YAG Laser and 6.5% were VR surgery. It is notable that a higher number of people suffered in ocular, cataract and retinal disorder respectively among all the eye disorders. With increasing patient age, the number of eye disorder treatments increased and it reached to peak number in the age group 56-60 years, although numbers varied greatly across age groups.

PURPOSE: To review and describe in detail the demographics, functional and anatomical characteristics, and clinical course of pigmented paravenous chorioretinal atrophy in a large cohort of adults and children. METHODS: This is a retrospective case series of consecutive patients diagnosed with pigmented paravenous chorioretinal atrophy at a single U.K. referral center from 1974 to 2016. Clinical records, retinal imaging (color fundus photography, fundus autofluorescence, and optical coherence tomography), and electrophysiological assessments were reviewed. RESULTS: Twenty-three patients were identified (13 males and 10 females). The mean age at presentation was 35 years (range 10-67 years). Mean follow-up was 6.7 years (range 0-30 years). There was no family history of similar retinal disease. Thirteen (57%) patients were asymptomatic. Symptoms included photopsia (n = 1.4%), blurred vision (n = 4.17%), peripheral visual field loss (n = 3.13%), and nyctalopia (n = 2.8%). One patient had previous intermediate uveitis. Twenty-one (91%) patients had ≥6/12 in the better seeing eye at final follow-up; visual acuity loss over time was recorded in 2 patients. Color vision was normal in all 14 patients assessed. Paravenous hypoautofluorescence with surrounding increased fundus autofluorescence was characteristically observed. Optical coherence tomography over the retinal changes demonstrated choroidal, retinal pigment epithelium, and outer retinal layer thinning. Peripapillary atrophic changes on fundus photography were evident in 20 (87%) patients. Interocular asymmetry of fundus and electroretinography findings was common. The electroretinography findings showed a similar degree of generalized rod and cone photoreceptor dysfunction in most cases. CONCLUSION: Overall, most patients with pigmented paravenous chorioretinal atrophy maintained stable vision. The lack of other affected family members, slow or absent progression, and interocular asymmetry of the retinal features is suggestive of an acquired rather than inherited retinal disorder, generally nonprogressive disorder. We identify that patients commonly have marked interocular asymmetry both on structural and functional assessment.

Retinal ischemia is a major cause of vision loss and impairment and a common underlying mechanism associated with diseases such as glaucoma, diabetic retinopathy, and central retinal artery occlusion. The regenerative capacity of the diseased human retina is limited. Our previous studies have shown the neuroprotective effects of intravitreal injection of mesenchymal stem cells (MSC) and MSC-conditioned medium in retinal ischemia in rats. Based upon the hypothesis that the neuroprotective effects of MSCs and conditioned medium are largely mediated by extracellular vesicles (EVs), MSC derived EVs were tested in an in-vitro oxygen-glucose deprivation (OGD) model of retinal ischemia. Treatment of R28 retinal cells with MSC-derived EVs significantly reduced cell death and attenuated loss of cell proliferation. Mechanistic studies on the mode of EV endocytosis by retinal cells were performed in vitro. EV endocytosis was dose- and temperature-dependent, saturable, and occurred via cell surface heparin sulfate proteoglycans mediated by the caveolar endocytic pathway. The administration of MSC-EVs into the vitreous humor 24 h after retinal ischemia in a rat model significantly enhanced functional recovery, and decreased neuro-inflammation and apoptosis. EVs were taken up by retinal neurons, retinal ganglion cells, and microglia. They were present in the vitreous humor for four weeks after intravitreal administration, with saturable binding to vitreous humor components. Overall, this study highlights the potential of MSC-EV as biomaterials for neuroprotective and regenerative therapy in retinal disorders.

Purpose: To describe the clinical and electrophysiological features of an unusual retinopathy in a patient with a novel genotype of CNGB1, mutations in which are implicated in autosomal recessive retinitis pigmentosa (rod-cone dystrophy). Observations: A 61-year old asymptomatic woman was referred to the inherited retinal disorders clinic because of peripheral retinal pigmentary changes. She had normal visual acuity and color vision. Clinical examination and detailed imaging of the macula were normal, but there was atrophy of the outer retina in the periphery with sparse intra-retinal pigmentation. Electroretinography (ERG) revealed undetectable rod responses, with normal cone-mediated responses. The pattern ERG was normal. Genetic analysis identified two previously unreported variants in CNGB1: (c.2258T > A, p.[Leu753*] and c.807G > C, p.[Gln269His]), shown to be in trans. Conclusions and importance: This report describes a functionally cone-isolated retina in an adult, apparently hemizygous for a novel missense mutation in CNGB1, a novel phenotype for this gene. The p.[Gln269His] allele is the first missense change, within the glutamic acid-rich protein (GARP) domain of CNGB1, to be associated with retinal disease in humans. Keywords: Cone-isolated retina, Cyclic nucleotide-gated channels, Glutamic-acid rich protein (GARP), Night blindness, Retinitis pigmentosa, Rod dysfunction

SIGNIFICANCE Optometrists, as primary eye care providers, encounter patients with rare ocular disease such as Bietti crystalline dystrophy from time to time. Using advanced technologies, which are also useful in managing common ocular conditions, to facilitate a prompt diagnosis is highly recommended. PURPOSE This report describes a patient with clinically diagnosed Bietti crystalline dystrophy with findings on funduscopy, multimodal imaging, and visual electrophysiology. CASE REPORT A 41-year-old Chinese woman who had subjectively progressing dimmed vision (especially in the left eye) for 9 months was referred to our clinic to test for retinitis pigmentosa. Best-corrected visual acuities were 6/6 and 6/7.6 in the right and left eyes, respectively. Funduscopy revealed multiple crystalline deposits on the posterior pole in both eyes. The 30-2 perimetry displayed bi-inferotemporal scotoma (left > right eye). Scotopic flash electroretinogram (ERG) yielded a normal result, whereas photopic ERG was slightly attenuated. Electro-oculogram showed an abnormal adaptation time course of the retinal pigmented epithelium (RPE). Multifocal ERG revealed a decreased central retinal response, but paracentral responses were relatively better preserved. Optical coherence tomography showed multiple patches of RPE atrophy, with disruption of the left ellipsoid zone. Outer retinal tubulations, hyperreflective dots on RPE-Bruch's membrane interface, and intraretinal bright spots were also identified. CONCLUSIONS Rare ocular diseases like Bietti crystalline dystrophy can be encountered by optometrists. This case report shows the ophthalmic findings of a rare chorioretinal dystrophy and provides insight on how to better use advanced equipment in an optometric practice to facilitate prompt diagnoses.

In degenerative retinal disorders, rod and cone photoreceptors die, causing vision impairment and blindness. Downstream neurons survive but undergo morphological and physiological remodeling, with some retinal ganglion cells (RGC) exhibiting heightened spontaneous firing. Retinoic acid (RA) has been implicated as the key signaling molecule that induces RGC hyperactivity, obscuring RGC light responses and reducing light avoidance behaviors triggered by residual rods and cones. However, evidence that RA-dependent remodeling corrupts image-forming vision has been lacking. Here we show that disulfiram, an FDA-approved drug that inhibits RA synthesis, and BMS 493, an RA receptor (RAR) inhibitor, reduce RGC hyperactivity and augment image detection in visually impaired mice. Functional imaging of visual cortical neurons shows that disulfiram and BMS 493 sharpen orientation-tuning and strengthen response fidelity to naturalistic scenes. These findings establish a causal link between RA-induced retinal hyperactivity and vision impairment and define molecular targets and candidate drugs for boosting image-forming vision in retinal degeneration.

We have developed a model with an intent of identifying the presence of each of three disorders, namely the Diabetic Macular Edema (DME), the Choroidal Neovascularization (CNV) and the Drusen, and if otherwise, then categorizing them as normal macula. OCT or Optical Coherence Tomography is a non-invasive imaging technique that produces high-resolution cross-sectional images of biological tissues. according to the literature survey, the identification of retinal disorders in OCT images of the retina is one of the most pressing issues in this domain. Keen on doing something about it we started researching and found that there have been very few recent publications in this domain on Deep Learning. Hence, we went ahead with working towards building a process of classifying the retinal disorders in OCT scans using Deep Learning. We have proposed a Deep-Learning-based detection system for the purpose of screening patients with blinding retinal diseases that can be treated if identified early. To achieve this, Convolutional Neural Network (CNN) is used. An accuracy of 99.38% with a precision amounting to 0.9938 is achieved. The Area Under Curve assesses to an average of 1.00.

SUMMARYCis-regulatory elements (CREs) play a critical role in the development, maintenance, and disease-states of all human cell types. In the human retina, CREs have been implicated in a variety of inherited retinal disorders. To characterize cell-class-specific CREs in the human retina and elucidate their potential functions in development and disease, we performed single-nucleus (sn)ATAC-seq and snRNA-seq on the developing and adult human retina and on human retinal organoids. These analyses allowed us to identify cell-class-specific CREs, enriched transcription factor binding motifs, putative target genes, and to examine how these features change over development. By comparing DNA accessibility between the human retina and retinal organoids we found that CREs in organoids are highly correlated at the single-cell level, validating the use of organoids as a model for studying disease-associated CREs. As a proof of concept, we studied the function of a disease-associated CRE at 5q14.3 in organoids, identifying its principal target gene as the miR-9-2 primary transcript and demonstrating a dual role for this CRE in regulating neurogenesis and gene regulatory programs in mature glia. This study provides a rich resource for characterizing cell-class-specific CREs in the human retina and showcases retinal organoids as a model in which to study the function of retinal CREs that influence retinal development and disease.HIGHLIGHTSSingle-cell map of cis-regulatory elements in developing and adult human retina.Correlation of single-cell DNA accessibility between human retina and retinal organoids.Association of disease risk loci with cell-class-specific accessibility.Modeling of enhancer function at the 5q14.3 retinal disease-risk locus.

Inherited retinal diseases (IRDs) are a genetically variable collection of devastating disorders that lead to significant visual impairment. Advances in genetic characterization over the past two decades have allowed identification of over 260 causative mutations associated with inherited retinal disorders. Thought to be incurable, gene supplementation therapy offers great promise in treating various forms of these blinding conditions. In gene replacement therapy, a disease-causing gene is replaced with a functional copy of the gene. These therapies are designed to slow disease progression and hopefully restore visual function. Gene therapies are typically delivered to target retinal cells by subretinal (SR) or intravitreal (IVT) injection. The historic Food and Drug Administration (FDA) approval of voretigene neparvovec for RPE65-associated Leber's congenital amaurosis (LCA) spurred tremendous optimism surrounding retinal gene therapy for various other monogenic IRDs. Novel disease-causing mutations continue to be discovered annually, and targeted genetic therapy is now under development in clinical and preclinical models for many IRDs. Numerous clinical trials for other IRDs are ongoing or have recently completed. Disorders being targeted for genetic therapy include retinitis pigmentosa (RP), choroideremia (CHM), achromatopsia (ACHM), Leber's hereditary optic neuropathy, usher syndrome (USH), X-linked retinoschisis, and Stargardt disease. Here, we provide an update of completed, ongoing, and planned clinical trials using gene supplementation strategies for retinal degenerative disorders.

Age-related Macular Degeneration (AMD) is a progressive, irreversible retinal disorder, and one of the leading causes of severe visual impairment or even blindness in the elderly population. The choroid plays a vital role in the pathophysiology of AMD. It is known that abnormal choroidal blood flow leads to retinal photoreceptor dysfunction and eventual death. We propose a new automated algorithm that can be used to quantify choroidal thickness (CT) from Optical Coherence Tomography (OCT) images of the retina. This thickness evaluation procedure includes image contrast enhancement, localization around the fovea centralis, segmentation of Retinal Pigment Epithelium (RPE) and choroidal layer, followed by CT measurement at multiple locations in the sub-foveal region at intervals of 0.5 mm on both nasal and temporal sides up to a distance of 1 mm from the center of the foveal pit. The horizontal radial scan OCT images (Cirrus 5000, Carl Zeiss Meditec Inc., Dublin, CA) of both healthy and AMD patients were used to measure the CT using the new algorithm. The statistical tests convey that the CT of AMD patients is relatively smaller than the normal condition. Furthermore, t-Test conducted between the proposed approach and clinical approach of extracting CT measurements confirm that the proposed method is in good agreement with the clinical measurements. On an average, the thickness of the choroid is found to be 0.32 ± 0.10 mm for the normal category and 0.21 ± 0.06 mm for the AMD category, in the central sub-foveal region, as obtained from the proposed automatic CT measurement method. The clinical significance and the results of automated choroid extraction are discussed in this paper.

Francesca Simonelli,1 Andrea Sodi,2 Benedetto Falsini,3,4 Giacomo Bacci,5 Giancarlo Iarossi,6 Valentina Di Iorio,1 Dario Giorgio,2 Giorgio Placidi,3,4 Assia Andrao,7 Luigi Reale,8 Alessandra Fiorencis,8 Manar Aoun9 1Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania “L. Vanvitelli”, Naples, Italy; 2Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy; 3UOC Oftalmologia, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy; 4Dipartimento Testa-collo e organi di senso, Università Cattolica del Sacro Cuore, Rome, Italy; 5Paediatric Ophthalmology Unit, Children’s Hospital “A. Meyer”, University of Florence, Florence, Italy; 6Ophthalmology Department, Bambino Gesù IRCCS Paediatric Hospital, Rome, Italy; 7Retina Italia Onlus Association, Milan, Italy; 8Healthcare Department, Fondazione ISTUD, Milan, Italy; 9Medical Department, Novartis Farma, Origgio, ItalyCorrespondence: Luigi RealeHealthcare Department, Fondazione ISTUD, via Paolo Lomazzo 19, Milano, 20124, ItalyTel +390323933801Email lreale@istud.itFrancesca Simonelli Tel +390817704501Email francesca.simonelli@unicampania.itPurpose: Timely detection and multidisciplinary management of RPE65-related inherited retinal disorders (IRDs) can significantly improve both disease management and patient care. Thus, this Narrative Medicine (NM) project aimed to investigate the evolution of the care pathway and the expectations on genetic counseling and gene therapy by patients, caregivers, and healthcare professionals.Patients and Methods: This project was conducted between July and December 2020, involving five Italian eye clinics specialized in IRDs, targeted pediatric and adult patients, their caregivers, attending retinologists and multidisciplinary healthcare professionals. Narratives and parallel charts, together with a sociodemographic survey, were collected through the project webpage. In-depth interviews were conducted with Patient Association (PA) members and multidisciplinary healthcare professionals. All data were entered into the Nvivo Software for coding and analysis.Results: Three pediatric and five adult patients with early-onset RPE65-related IRDs as well as eight caregivers were enrolled; 11 retinologists globally wrote 27 parallel charts; in-depth interviews were done with five multidisciplinary healthcare professionals and one PA member. Early diagnosis remains challenging, and patients reported to have changed up to 10 healthcare professionals before accessing their specialized center. Despite the oftentimes lack of awareness of patients and caregivers on the purpose of genetic testing, participants generally consider gene therapy as a therapeutic chance and a historic breakthrough for the management of RPE65-related IRDs. Well-organized networks to support the patient’s referral to specialized centers – as well as a proper communication of the clinical and genetic diagnosis and the multidisciplinary approach – emerge as crucial aspects in facilitating an early diagnosis and management and a timely initiation of the rehabilitation pathway.Conclusion: The project investigated the RPE65-related IRDs care pathway while integrating the different perspectives involved through NM. The analysis explored the patient’s pathway in Italy and confirmed the need for a well-organized network and multidisciplinary care while highlighting several preliminary areas of improvement in the management of RPE65-related IRDs.Keywords: IRDs management, multidisciplinary, inherited retinal dystrophies, diagnosis, patient’s pathway

Retinitis Pigmentosa is a genetically heterogeneous, degenerative retinal disorder characterized by gradual dysfunction and death of photoreceptors, first rods and later cones, and progressive blindness. Studies suggested that application of L-type calcium channel blockers rescues photoreceptors in paradigms related to Ca2+ overflow. To investigate whether Cav1.3 L-type channels have protective effects in the retina, we established a new mouse model by crossing rd10, modeling autosomal-recessive RP, with Cav1.3 deficient mice (rd10/Cav1.3KO). Our immunohistochemical analyses revealed an influence of Cav1.3 channels on the degenerative process of photoreceptors. The absence of Cav1.3 delayed the centre-to-periphery degeneration of rods indicated by a significantly higher number of photoreceptor rows and, consequently, of cones. In accordance with a preserved number of cones we observed a regular row of cone somas in rd10/Cav1.3-KO retinas. Surviving rod photoreceptors maintained synaptic contacts with rod bipolar cells. However, the delay in degeneration was only observed up to postnatal day 45. Although we observed a reduction in the spontaneous oscillatory retinal activity during multielectrode array analyses, measurable functional preservation was lacking in behavioural tests. In conclusion, Cav1.3 channels contribute to photoreceptor degeneration in rd10 retinas but photoreceptor temporary rescue might rather be achieved indirectly through other retinal cell layers.