Pathophysiology of aniridia-associated keratopathy: Developmental aspects and unanswered questions

Aniridia, a rare congenital disease, is often characterized by a progressive, pronounced limbal insufficiency and ocular surface pathology termed aniridia-associated keratopathy (AAK). Due to the characteristics of AAK and its bilateral nature, clinical management is challenging and complicated by the multiple coexisting ocular and systemic morbidities in aniridia. Although it is primarily assumed that AAK originates from a congenital limbal stem cell deficiency, in recent years AAK and its pathogenesis has been questioned in the light of new evidence and a refined understanding of ocular development and the biology of limbal stem cells (LSCs) and their niche. Here, by consolidating and comparing the latest clinical and preclinical evidence, we discuss key unanswered questions regarding ocular developmental aspects crucial to AAK. We also highlight hypotheses on the potential role of LSCs and the ocular surface microenvironment in AAK. The insights thus gained lead to a greater appreciation for the role of developmental and cellular processes in the emergence of AAK. They also highlight areas for future research to enable a deeper understanding of aniridia, and thereby the potential to develop new treatments for this rare but blinding ocular surface disease.     

A Review of the Clinical and Genetic Aspects of Aniridia

Abstract

Aniridia classically presents with a bilateral congenital absence or malformation of the irides, foveal hypoplasia, and nystagmus, and patients tend to develop visually significant pre-senile cataracts and keratopathy. Additionally, they are at high risk for developing glaucoma. Classic aniridia can be genetically defined as the presence of a PAX6 gene deletion or loss-of-function mutation that results in haploinsufficiency. Variants of aniridia, which include a condition previously referred to as autosomal dominant keratitis, are likely due to PAX6 mutations that lead to partial loss of PAX6 function. Aniridia-associated keratopathy (AAK) is a progressive and potentially debilitating problem affecting aniridic patients. The current treatments for AAK are to replace the limbal stem cells through keratolimbal allograft (KLAL) with or without subsequent keratoplasty for visual rehabilitation, or to implant a Boston type 1 keratoprosthesis. Future therapies for AAK may be aimed at the genetic modification of corneal limbal stem cells.     

In vivo confocal microscopy of congenital aniridia-associated keratopathy

Purpose

To explore the in vivo morphological changes of cornea and limbus in aniridia-associated keratopathy (AAK).

Methods

Three cases of AAK were examined with the application of in vivo confocal microscopy (IVCM).

Results

Abnormal structure of wing and basal layer of epithelium, the loss of subbasal nerves, and the presence of goblet cells at central cornea could be identified in the most severe case, along with the absence of Vogt palisades. The less extent of abnormalities in corneal epithelial cells, subbasal nerve, and Vogt palisades were visible in the moderate or mild cases.

Conclusions

The morphological changes of cornea and limbus vary in AAK, and IVCM is a promising tool to determine the degree of limbal stem cell deficiency in patients with AAK.     

从VEGF在湿性年龄相关性黄斑变性发病过程中的作用机制看抗VEGF药物治疗

年龄相关性黄斑变性(AMD)的发病机制较复杂,其中湿性AMD对视力的威胁更为严重,其主要病理特征是黄斑区脉络膜的新生血管形成,血管内皮细胞生长因子( VEGF)在发病和新生血管的发展过程中发挥着重要作用.湿性AMD的物理治疗方法较多,但均无法改善患者的视力,近年来拮抗VEGF作用的药物疗法成为湿性AMD治疗的新途径.抗VEGF单克隆抗体是目前临床上应用较多的药物,能够消除新生血管,改善患者视力.针对VEGF其他环节的药物,如VEGF捕获剂、小分子干扰RNA及酪氨酸激酶抑制剂等,正处于试验阶段,其治疗效果值得期待.由于这些药物均为抗VEGF的制剂,因此充分了解VEGF在湿性AMD发病和发展过程中的作用机制有助于合理使用这些药物.     

Leber遗传性视神经病变的治疗进展

Leber遗传性视神经病变是一种双眼进行性视力下降的遗传性线粒体病.当前治疗主要包括直接增强线粒体功能和阻止氧化损伤.本文将从线粒体鸡尾酒、艾地苯醌、α-三烯酶醌、溴莫尼定、中医中药、基因治疗、限制烟酒及物理疗法7个方面的治疗进展进行综述,进而为治疗Leber遗传性视神经病变提供思路.     

玻璃体切割术后继发青光眼的病因及治疗

继发性青光眼（secondary glaucoma,SG）是玻璃体切割术术后的并发症之一,其病因机制繁多。如不及时有效处理,可导致视神经不可逆性损伤、视野缺损,甚至视力丧失。目前此病在国内外比较重视并有一定的报道,本文就玻璃体切割术后继发性青光眼的病因病理机制及治疗手段,进行总结分析如下。     

Stage-related central corneal epithelial transformation in congenital aniridia-associated keratopathy

Purpose

To relate central corneal epithelial phenotype to degree of keratopathy in a limbal stem cell deficient population.

【In Press】 Current approaches and future directions in the management of pterygium

Pteryium, a common ocular surface disorder, has a complex pathophysiology that may mimic tumorigenesis. There is altered expression of cell cycle/proliferation-related factors in pterygium tissues. Therefore, similar to cancer treatments, the management of pterygium ought to be multifactorial based on the patient''s condition. Current therapeutic methods for pterygium are focused on surgical resection in conjunction with antimetabolite use, in addition tissue graft is usually performed in the context of the avoidance of bare sclera. However, future directions in the management of pterygia will likely focus on genetic approaches. This perspective views the pathogenesis of pterygium, its existing therapies as well as current and future challenges in its treatment.     

Cancer-Associated Retinopathy: Update on Pathogenesis and Therapy

Paraneoplastic retinopathies comprise a diverse group of immune-mediated conditions affecting the eye. Cancer-associated retinopathy (CAR) typically has a sudden onset of severe visual loss and an ominous association with an occult malignancy. CAR is one of the best studied and better understood conditions in the multifarious group of autoimmune retinopathies. Recent developments have correlated the disease presentation, course, and therapeutic response to the underlying immune mediators and the inciting antigens. Signaling involving cytotoxic T-lymphocytes antigen 4 (CTLA-4) and vascular endothelial growth factor (VEGF) receptor-1 appears to play a role in the pathogenesis and may offer novel avenues for therapeutic intervention in CAR. Future developments in rapid identification and longitudinal quantification of antibody levels would enable individualized management in these patients. The goal of this review is to analyze the clinical features of diagnosis and management of retinopathy in the context of recent advances in the elucidation of CAR pathogenesis.     

Pterygia: Pathogenesis and the Role of Subconjunctival Bevacizumab in Treatment

A pterygium is a very common conjunctival degenerative condition. It has been well established that there are different factors that are interrelated and involved in the growth of pterygia. Historically described more as a degenerative process, inflammation and fibrovascular proliferation have proven to be very important factors. Many studies have shown VEGF to be increased in the pathogenesis of pterygia. There are a variety of options for the management of pterygium. The over expression of VEGF in pterygium tissue led us to develop anti-angiogenic/anti-VEGF therapy which could induce regression of blood vessels and hence retard progression of pterygium. The role of angiogenesis and of VEGF in ocular pathology is established including in corneal neovascularization, specifically in pterygial tissue. Evidence suggests that local bevacizumab may be effective in treatment of ocular surface neovascularization. Currently, data in the use of subconjunctival bevacizumab in the treatment of pterygia are not conclusive. New anti-angiogenic therapies will hopefully focus more on facilitating delivery into tissue, increasing the duration of effect while continuing to minimize adverse side effects.     

角膜新生血管治疗的研究进展

角膜新生血管( corneal neovascularization ,CNV)是由维持角膜无血管的平衡因素被破坏,角膜缘的毛细血管侵入无色清亮的角膜组织导致。 CNV是国内较常见的致盲眼病之一,近年来,尽管免疫学、细胞分子生物学和药理学等学科发展让我们对CNV的发病因素及治疗的认识有不少突破,但病因多样缺乏总结,且迄今为止,对CNV的治疗尚无特效疗法。本文将简要阐述CNV的病因、发病机制,着重总结CNV的治疗进展。     

湿性年龄相关性黄斑变性治疗方法的新选择

湿性年龄相关性黄斑变性(AMD)是导致AMD患者视力丧失的主要原因,抗血管内皮生长因子(VEGF)的药物治疗可达到提高患者视力、减少AMD致盲率的目的,目前已成为治疗湿性AMD的一线用药.但在AMD的发病和进展过程中,脉络膜新生血管(CNV)的形成是复杂的、综合的病理过程,单纯的抗VEGF治疗并不能达到治愈所有湿性AMD的目的,因此对CNV形成各个信号途径的靶向治疗药物已进入各期临床试验阶段.除此之外,小干扰RNA技术、基因组学技术也被用于湿性AMD的治疗,其中基因治疗和干细胞治疗更值得关注,这些新的治疗手段无疑为湿性AMD的治疗提供了新的选择.     

Aniridia: current pathology and management

Aniridia is a rare panocular disorder affecting the cornea, anterior chamber, iris, lens, retina, macula and optic nerve. It occurs because of mutations in PAX6 on band p13 of chromosome 11. It is associated with a number of syndromes, including Wilm’s tumour, bilateral sporadic aniridia, genitourinary abnormalities and mental retardation (WAGR) syndrome. PAX6 mutations result in alterations in corneal cytokeratin expression, cell adhesion and glycoconjugate expression. This, in addition to stem‐cell deficiency, results in a fragile cornea and aniridia‐associated keratopathy (AAK). It also results in abnormalities in the differentiation of the angle, resulting in glaucoma. Glaucoma may also develop as a result of progressive angle closure from synechiae. There is cataract development, and this is associated with a fragile lens capsule. The iris is deficient. The optic nerve and fovea are hypoplastic, and the retina may be prone to detachment. Aniridia is a profibrotic disorder, and as a result many interventions – including penetrating keratoplasty and filtration surgery – fail. The Boston keratoprosthesis may provide a more effective approach in the management of AAK. Guarded filtration surgery appears to be effective in glaucoma. Despite our increasing understanding of the genetics and pathology of this condition, effective treatment remains elusive.     

Molecular Basis of Pterygium Development

Pterygium pathogenesis is mainly related to UV light exposure. However, the exact mechanisms by which it is formed have not been elucidated. Clinical advances in surgical treatment use conjunctival autografts and amniotic membranes in combination with adjuvant therapies, including mitomycin C, β-radiation, and 5-fluoroacil, to reduce recurrence. Several studies aim to unveil the molecular mechanisms underlying pterygium growth and proliferation. They demonstrate the role of different factors, such as viruses, oxidative stress, DNA methylation, apoptotic and oncogenic proteins, loss of heterozygosity, microsatellite instability, inflammatory mediators, extracellular matrix modulators, lymphangiogenesis, cell epithelial-mesenchymal transition, and alterations in cholesterol metabolism in pterygium development. Understanding the molecular basis of pterygium provides new potential therapeutic targets for its prevention and elimination. This review focuses on providing a broad overview of what is currently known regarding molecular mechanisms of pterygium pathogenesis.     

Early phenotypic features of aniridia-associated keratopathy and association with PAX6 coding mutations

PurposeTo investigate corneal phenotype in aniridia-associated keratopathy (AAK) including its earliest manifestations, in relation to PAX6 mutational status.Methods46 subjects (92 eyes) with congenital aniridia from a German registry were examined using slit lamp biomicroscopy, anterior segment optical coherence tomography, contact esthesiometry and in vivo confocal microscopy. Cytogenetic analysis was conducted by Sanger sequencing of PAX6 exons and/or MLPA analysis. Measured parameters included AAK grade, distance-corrected visual acuity (DCVA), central corneal thickness (CCT), corneal sensitivity, subbasal nerve density, mature dendritic cell (DC) density and corneal epithelial phenotype.Results46 subjects (age range: 1–64 years) were examined, including 23 (50%) children under the age of 18. Five subjects (11.1%) with absent PAX6 coding mutation (non-PAX6 cases) had mild AAK (Grade 0–1) into the fourth decade of life and maintained corneal epithelial phenotype, greater subbasal nerve density (16.8 mm/mm² vs. 3.58 mm/mm², P = 0.01) and better corneal sensitivity (41 ± 11 mm vs. 28 ± 12 mm, P = 0.03) relative to those with PAX6 coding mutations. In five subjects, corneal endothelial cell density ranged from 3245 to 4399 cells/mm². Independent of mutational status, an increased CCT, over tenfold increased mature DC density and reduced corneal sensitivity characterized all subjects.ConclusionsPAX6 coding mutations influence AAK phenotype and progression from the earliest stages of life. A minimal keratopathy present in 100% of congenital aniridia cases is independent of the specific mutation and consists of increased corneal thickness, reduced touch sensitivity, and increased ocular surface immune activity.     

Drug-induced Uveitis in HIV Patients with Ocular Opportunistic Infections

ABSTRACT

Purpose: To describe drug-induced uveitis in immunocompromised patients diagnosed with Human Immunodeficiency Virus (HIV) infection

Methods: Narrative Review

Results: Systemic and intraocular medications administered for the treatment of acquired immune deficiency syndrome (AIDS)-associated diseases in patients infected with HIV are a well-known cause of uveitis.

Conclusions: Cidofovir and rifabutin, among other novel anti-retroviral therapies, are strongly associated with drug-induced uveitis. It is imperative to understand the pathogenesis, clinical findings, and management of HIV patients with uveitis induced by these agents.     

Neovascular glaucoma

Neovascular glaucoma (NVG) is a severely blinding, intractable disease. The objective of this review is to provide detailed information on its basic and clinical aspects, to enable us to manage it logically. Therefore, its causes, pathogenesis and pathology, methods of early diagnosis and management are discussed. To prevent or reduce the extent of visual loss caused by NVG, the first essential is to have a high index of suspicion of its development. The most common diseases responsible for development of NVG are ischemic central retinal vein occlusion (CRVO), diabetic retinopathy and ocular ischemic syndrome. In the management strategy, the first priority should be to try to prevent its development by appropriate management of the causative diseases. If NVG develops, early diagnosis is crucial to reduce the extent of visual loss. Management of NVG primarily consists of controlling the high IOP by medical and/or surgical means to minimize the visual loss. Currently, we still do not have a satisfactory means of treating NVG and preventing visual loss in the majority, in spite of multiple modes of medical and surgical options advocated over the years and claims made. This review discusses the pros and cons for the various advocated treatments.     

Medical management of thyroid eye disease

Thyroid eye disease (TED) is the most common cause of orbital disease in adults. The immunologic pathogenesis of TED has been an area of active research and considerable progress has resulted in an expansion of therapeutic options. Although surgical intervention may be required, a majority of TED patients can be managed with medical therapies. Of medical therapies, glucocorticoids remain the agent of choice in the control of TED activity. The objective of this review is to discuss the paradigm and options in medical management of TED.     

持续性角膜上皮缺损的发病机制和诊疗新进展

角膜单纯疱疹病毒感染、角膜移植术后及糖尿病患者眼内手术后,可发生持续性角膜上皮缺损(persistent corneal epithelial defect, PED)。尽管其发病率不高,但若处理不当,可引起严重后果,如继发引起角膜感染或加重、基质溃疡、穿孔、瘢痕甚至视力丧失。PED的致病原因多样,可由多种机制介导。在临床上,即使对PED进行了积极的治疗,角膜上皮仍可能难以愈合,在治疗中具有一定挑战性。目前,对于PED的治疗,标准治疗方法主要包括使用绷带镜和人工泪液,旨在为角膜上皮层提供屏障保护; 而新型治疗方法主要针对上皮再生和角膜神经重新支配; 此外,近年来还涌现了一些有潜在治疗价值的药物和方法。在这篇综述中,我们讨论了PED的流行病学、病因、诊断和治疗,重点介绍了一些新型治疗方法及研究进展。     

年龄相关性黄斑变性脉络膜新生血管的治疗策略

年龄相关性黄斑变性(AMD)脉络膜新生血管形成(CNV)的治疗一直是眼科的难题之一。CNV引起黄斑区渗出、出血、纤维瘢痕形成,导致视力丧失。近年来,随着科学技术的发展,出现了一些新的治疗方法及手段。光动力疗法的出现突破了黄斑中心凹治疗的禁区,糖皮质激素、血管内皮生长因子抑制剂治疗和联合治疗给患者视力提高带来了曙光,经瞳孔温热疗法及手术治疗等也在探讨中,并取得了一定的疗效。但新疗法的有效性尚需多中心、大样本的随机临床试验来证实。