The purpose of this review is to provide a comprehensive and updated overview of the clinical features, imaging modalities, differential diagnosis, diagnostic criteria, and treatment options for Vogt-Koyanagi-Harada (VKH) syndrome, a rare progressive inflammatory condition characterized by bilateral granulomatous panuveitis and systemic manifestations. While the clinical features and disease course of VKH syndrome are well-characterized in the literature, its diagnosis is challenging due to a broad differential that include infectious and noninfectious causes of uveitis and rare inflammatory conditions, as well as a lack of a single diagnostic finding on exam, laboratory testing, or imaging. The evolution of the diagnostic criteria for VKH syndrome reflects the growing understanding of the disease by the ophthalmic community and advancement of imaging technology. Findings on enhanced depth imaging (EDI) optical coherence tomography (OCT) and indocyanine green angiography (ICGA) help detect subtle inflammation of the choroid and were incorporated into new diagnostic criteria developed in the last few years. There is limited research on the treatment for acute VKH, but results of studies to date support the early initiation of immunomodulatory therapy (IMT) due to a high recurrence rate and progression to chronic disease in patients treated with monotherapy with high-dose systemic corticosteroids. This review will provide an in-depth summary of recent literature on advanced imaging modality and IMT to guide clinicians in their management of patients with VKH syndrome.

Background: A variety of experimental animal models are used in basic ophthalmological research to elucidate physiological mechanisms of vision and disease pathogenesis. The choice of animal model is based on the measurability of specific parameters or structures, the applicability of clinical measurement technologies, and the similarity to human eye function. Studies of eye pathology usually compare optical parameters between a healthy and altered state, so accurate baseline assessments are critical, but few reports have comprehensively examined the normal anatomical structures and physiological functions in these models.

Methods: Three cynomolgus monkeys, six New Zealand rabbits, ten Sprague Dawley (SD) rats, and BALB/c mice were examined by fundus photography (FP), fundus fluorescein angiography (FFA), and optical coherence tomography (OCT).

Results: Most retinal structures of cynomolgus monkey were anatomically similar to the corresponding human structures as revealed by FP, FFA, and OCT. New Zealand rabbits have large eyeballs, but they have large optic disc and myelinated retinal nerve fibers in their retinas, and the growth pattern of retinal vessels were also different to the human retinas. Unlike monkeys and rabbits, the retinal vessels of SD rats and BALB/c mice were widely distributed and clear. The OCT performance of them were similar with human beings except the macular.

Conclusions: Monkey is a good model to study changes in retinal structure associated with fundus disease, rabbits are not suitable for studies on retinal vessel diseases and optic nerve diseases, and rats and mice are good models for retinal vascular diseases. These measures will help guide the choice of model and measurement technology and reduce the number of experimental animals required.

Abstract: Four challenging and unusual retinal cases: (I) 11-year follow-up for retinal hemangioblastoma with von Hippel-Lindau (VHL) disease; (II) treatment for central serous chorioretinopathy (CSC)—observation, half does photodynamic therapy (PDT) or micropulse laser photocoagulation; (III) diagnosis and treatment for a child with optic nerve defect; (IV) the optional treatment for retinal detachment (RD) with iridolenticular choroidal coloboma, were presented and discussed by three international retinal specialists at a retinal clinical round in Fundus Diseases Center of Zhongshan Ophthalmic Center (ZOC). The discussion helps us a better understanding of the pathogenesis and managements of these four retinal diseases and their association with systemic conditions.

Abstract: Primary vitreoretinal lymphoma (PVRL), as a subset of primary central nervous system lymphoma (PCNSL), is a rare and fatal ocular malignancy. Most PVRL masquerades as chronic posterior uveitis, which makes the clinical diagnosis challenging. Vitreous cells, subretinal lesions and imaging techniques are essential for clinical diagnosis. Importantly, cytopathology/histopathology identification of malignant cells is the gold standard for the diagnosis of PVRL. In addition, molecular detection of immunoglobulin heavy chain (IgH) or T cell receptor (TCR) gene rearrangements, immunophenotyping for cell markers, and cytokine analysis of interleukine-10 elevation are often used as adjunct procedures. Current management of PVRL involves local radiation, intravitreal chemotherapy (methotrexate and rituximab), with or without systemic chemotherapy depending on the involvement of non-ocular tissues. In cases with concomitant PCNSL, systemic high-dose methotrexate/rituximab based therapy in conjunction with local therapy, whole brain radiotherapy and/or autologous stem cell transplantation is considered. Although PVRL normally responds well to initial treatment, high rates of relapse and CNS involvement usually lead to poor prognosis and limited survival. A professional team of medical experts in ophthalmologists, ocular pathologists, neuro-oncologists and hemato-oncologists is essential for optimizing patient management.

Abstract: Vision loss in retinal disease is often secondary to neural cell loss. Neural loss of any type including that of the retina has always been considered irreversible as these cells rarely retain the ability to regenerate. The recent identification of stable stem cell sources and the advances in stem cell technology have transformed this area of research science into an important area of strong therapeutic possibility. These sources include human embryonic stem cells (hESC), induced pleuripotent stem cell sources (iPS) as well as adult sources. The main advantage of using a stem cell source is that there is an infinite capacity to reproduce and therefore an infinite capacity to produce cells, including neural cells for transplantation. The challenge more recently has been to transform these stem cells into differentiated cells that are useful for transplantation in disease. In terms of the retina, hESC have been successfully developed into retinal pigment epithelial cells. These cells have been characterised as identical to native human RPE cells structurally, functionally and biochemically. Previous studies of macular translocation and RPE/choroidal transplantation have shown that vision loss from AMD can be reversed. Early animal studies show that the transplanted HESC RPE survive and can prevent vision loss in animal models of disease. Initial hESC based RPE transplantation trials using suspension cultures were successful in demonstrating safety of the cells in the context of disease and sub-retinal delivery. More recently, we have carried out the first 2 transplantations of sheets of hESC based RPE on a coated artificial Bruch’s membrane, in the London Project’s RPE transplantation trial, with promising results. As well as RPE— Bruch’s transplantation I will also briefly discuss the recent advances in neuro-retinal and vascular reconstructions using stem cells.

Abstract: Blinding diseases such as photoreceptor degenerations are debilitating conditions that severely impair daily lives of affected patients. This group of diseases are amenable to photoreceptor replacement therapies and recent transplantation studies provided proof-of-principle for functional recovery at the retinal and behavioral level, though the actual mechanism of repair still needs further investigations. The immune system responds in several ways upon photoreceptor engraftment, resulting in T-cell and macrophage infiltrations and, consequently, decrease in graft survival. Most studies on the role of the immune system suggest a detrimental effect in a therapeutic setting. Conversely, the opposite idea wherein the immune system can be activated towards a protective state was also explored in other experimental paradigms. Here, Neves and colleagues explored the potential of cross-species studies and, to a certain extent, the concept of a protective immune system in retinal degeneration and therapy. Mesencephalic astrocyte-derived neurotrophic factor (MANF) was identified in this study as a novel factor that, by modulating the immune system, can slow down photoreceptor degeneration and improve transplantation outcome.

Abstract: The article discusses the early abandonment of mechanical theories about eye enlargement in degenerative myopia at the turn of the 20th century. At that time, the number of theories about myopia grew unrestricted, but with scant support from the experimental field. The mechanical theories vanished as a new wave of metabolism-based theories appeared, propelled by the huge advances in molecular biology. Modern techniques allow reconsidering those theories and to put them to test with higher confidence.

Background: Retinal pigment epithelium (RPE) is vital for the homeostasis of the subretina including photoreceptors and choroid. Interestingly, our previous results suggested that the recently discovered lactate receptor GPR81 is abundantly expressed in RPE. To date, only one previous study has shown that activating GPR81 could enhance DNA repair by activating HDAC1. Consequently, we investigated whether GPR81 exhibits epigenetic modification in the subretina by using GPR81?/? mice.

Methods: GPR81?/? mice and wide type littermates were generated on a background of C57BL/6J mice. The thicknesses of their choroid were evaluated by immunohistochemistry. Meanwhile, Q-PCR, western blot and choroid sprout assay were performed. In vitro, primary retinal pigment epithelium (pRPE) cells were isolated from mice, and cultured for treatments.

Results: The thickness of choroid was reduced in GPR81?/? mice compared to GPR81+/+ mice, suggesting that GPR81 is important for the integrity of choroid. In the choroid sprout assay, lactate treated RPE/choroid complex showed a significant increase in angiogenesis compared to controls while lactate treated KO RPE/choroid complex showed no difference compared to their controls. For Q-PCR, most of the genes screened elevated their expression in GPR81?/? mice compared to WT mice, suggesting epigenetic modification may exist, which were confirmed by histone acetylation and HDACs activity assay.

Conclusions: Taking together, the lactate receptor GPR81 in RPE is very important for maintaining homeostasis of the subretina. This novel discovery sheds new light on the relationship between metabolism and epigenetic modification.