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.     

Cancer Associated Retinopathy (CAR): An Autoimmune-Mediated Paraneoplastic Syndrome

Cancer associated retinopathy (CAR) is an uncommon paraneoplastic retinopathy in which antibodies are directed against retinal antigens. Vision loss is associated with abnormal ERG findings. Few case reports and lack of controlled clinical trials make management of this syndrome especially challenging for the clinician. Herein, we describe the clinical, histopathologic and electrophysiologic features of CAR, along with a summary of previously employed management options. Cancer associated retinopathy syndrome has been recognized as a paraneoplastic disorder, most commonly associated with small cell lung cancer, in which cross-reacting autoantibodies against retinal antigen cause retinal dysfunction. Bilateral vision loss as a result of both rod and cone dysfunction in CAR may occur over a period of months, and visual symptoms may precede diagnosis of the systemic malignancy. The heterogeneity in antigens that have been identified as targets of antibody-mediated retinal damage perhaps help to explain the complexity of symptoms and the treatment challenges posed by patients with CAR.     

自身免疫性视网膜病变血清抗视网膜抗体的检测

目的 探讨自身免疫性视网膜病变（autoimmuneretinopathy,AIR）患者血清抗视网膜抗体（anti-retinal antibodies, ARA）检测的临床应用价值。设计 前瞻性比较性病例系列。研究对象 临床疑似AIR患者、健康人对照及其他视网膜病变对照包括原发性视网膜色素变性（retinitis pigmentosa,RP）、双眼葡萄膜炎、白点综合征患者。方法 选取2016年9月-2018年5月北京同仁医院就诊的临床疑似AIR患者17例作为实验组,健康人20例作为对照组,RP患者18例、双眼葡萄膜炎患者9例、白点综合征患者6例作为其他视网膜病变对照组。通过免疫印迹法检测各组受检者血清 ARA,比较各组的阳性率及差异。主要指标 血清恢复蛋白（recoverin）,烯醇化酶α（α-enolase）,碳酸酐酶II（carbonic anhydraseII,CAII）,塌陷反应介导蛋白5（collapsin response mediator protein 5,CRMP5）抗体。结果 临床疑似AIR组、其他视网膜病变对照组及健康人部分受试者血清中均有不同种类ARA检出。一种或两种以上抗体表达阳性率在临床疑似AIR组分别为76.5%及64.7%,在其他视网膜病变对照组分别为54.5%及30.3%,在健康受试者分别为33.3%及0%。RP患者抗体阳性率为33.3%。各组中以α-enolase及CA II抗体表达阳性率最高;recoverin抗体特异性存在于癌症相关性视网膜病变患者（cancer-associated retinopathy, CAR）血清中。结论 临床疑似AIR患者血清中ARA存在率较高,明显高于健康人及RP患者;二个以上ARA表达明显高于其他视网膜病变,故对该疾病具有重要辅助诊断价值。血清ARA的存在必须与临床体征结合才能确诊AIR。     

Retinopathy of Prematurity: Current Concepts in Molecular Pathogenesis

Retinopathy of prematurity is marked by the proliferative vascularization of the retina in preterm babies. An understanding of the molecular pathogenesis of ROP provides the basis for identifying novel therapeutic targets for treatment. Using the mouse model of oxygen-induced retinopathy, the roles of the hypoxia induced factors vascular endothelial growth factor and erythropoietin as well as the maternally derived factors insulin-like growth factor-1 and omega-3 polyunsaturated fatty acids have begun to be elucidated. Understanding the phase specific effects of these factors will serve to guide the development of non destructive treatments for ROP and for other ischemic retinopathies including diabetic retinopathy and neovascular age-related macular degeneration.     

Cancer-associated retinopathy (CAR) with electronegative ERG: a case report

Cancer-associated retinopathy (CAR) should be suspected in patients who present with visual symptoms such as rapid unexplained visual loss and seeing shimmering lights, with an abnormal ERG. Electronegative ERG responses are not exclusive to melanoma-associated retinopathy (MAR) but may be seen in CAR as well. We describe a patient with CAR who presented with an electronegative ERG. A 67-year old woman, who presented with complaints of seeing shimmering lights, underwent an extensive ophthalmological and electrophysiological examination. Best-corrected visual acuity was 7/10 in the right and 9/10 in the left eye. Goldmann visual fields showed relative central scotomata and concentric narrowing. Slit-lamp and fundus examination were normal as was fluorescein angiography. Rod-specific ERG responses were severely reduced, with electronegative maximal combined rod-cone responses and delayed cone-responses with normal amplitudes. Melanoma-associated retinopathy was suspected. Extensive dermatological and internal evaluation eventually revealed an oat-cell carcinoma in the right lung. The patient died of pneumonia 2 years after presentation.     

Experimental,cancer-induced retinopathy

Autoantibody reactions with various ocular components have been described in different types of paraneoplastic vision loss, and are considered indicators of an activated, and potentially harmful immunologic process. To date, only one subgroup, the 23 kd CAR syndrome, has been linked with hypersensitivity to a single defined retinal protein, recoverin. Inquiries into the cause of this unusual immunologic reaction led to the discovery that this photoreceptor component is expressed by some, but not all small cell carcinomas, the neoplasm most often linked with paraneoplasias. Neoplasia expressing retinal antigens, outside normal distribution, may provoke an immune response resulting in a cancer-induced autoimmune retinopathy, a cause and effect relationship addressing the etiology and pathogenesis of the CAR syndrome. Since only a subset of paraneoplastic retinopathy patients produce autoantibodies reactive with the 23 kd CAR autoantigen, a search was initiated in other subgroups, seeking additional examples of this immunologic cancer connection.

Cultures of small cell lung carcinomas were obtained from the American Type Culture Collection, Human Tumor Bank (ATCC, HTB), each expressing the unique characteristics of the donor. The ability of single cultures to incite the production of anti-retinal antibodies in laboratory animals was investigated through intraperitoneal propagation in ‘Pristane’ induced ascites, followed by an evaluation of the resultant immunologic response.

A culture of small cell carcinoma of the lung, the HTB 175, was found actively expressing a novel retinal protein corresponding in Western blot analyses to that involved in the autoantibody reactions of an immunologically distinct subgroup of paraneoplastic retinopathy patients.     

Presumed CMV associated necrotizing retinopathy in a non-HIV immunocompromised host

Herpetic necrotizing retinitis is caused by the herpesvirus group of viruses, including cytomegalovirus (CMV). Reports defining causative viruses have shown CMV to be a rare cause of acute retinal necrosis. In fact, there is only one report in the literature of CMV associated with progressive outer retinal necrosis, which is most commonly associated with Varicella zoster virus. A case is presented of CMV-related necrotizing retinopathy concurrent with subtle signs of herpetic retinitis in an immunocompromised patient, highlighting the spectrum of response of herpetic retinopathies.     

半導體激光光凝治療糖尿病性視網膜病變臨床分析

目的總結半導體激光光凝治療糖尿病性視網膜病變的體會.方法回顧性分析我院應用VIRIDIS532nm半導體激光泵浦的眼科黄绿激光治療糖尿病性視網膜病變116祗眼的臨床資料.結果激光光凝術後糖尿病性視網膜病變患者視力穩定或進步者達79.25%.結論根據糖尿病性視網膜病變的程度選擇合適的光凝術,確保高比例的視綱膜有效光斑是光凝術成功的關鍵.     

Crystalline retinopathy: Unifying pathogenic pathways of disease

Crystalline retinopathies may be associated with different etiologies including genetic, toxic, degenerative, idiopathic, and iatrogenic causes. We outline the various types of crystalline retinopathies and summarize their associated etiologies, pathogenesis, clinical presentations, multimodal imaging findings, and management strategies.     

VEGF在糖尿病性视网膜病变发病机制中的作用及抗VEGF治疗新进展

糖尿病性视网膜病变是世界新发致盲因素之一。血管内皮生长因子（ｖａｓｃｕｌａｒｅｎｄｏｔｈｅｌｉａｌｇｒｏｗｔｈｆａｃｔｏｒ,ＶＥＧＦ）是糖尿病性视网膜病变发病机制中的关键因子,成为近年研究的热点。近年来,抗ＶＥＧＦ药物成为新生血管性及血管性眼底疾病的重要治疗药物,本文就ＶＥＧＦ在糖尿病性视网膜病变病理进程中的作用及抗ＶＥＧＦ治疗新进展作一综述。     

Pathological changes in human retinal ganglion cells associated with diabetic and hypertensive retinopathy

Background To examine whether systemic diseases like diabetes and arterial hypertension, which frequently cause retinopathies leading to blindness effect the morphology of retinal ganglion cells (RGC). Methods Histological retina material with a history of being untreated, or laser-coagulated (LC) diabetic retinopathy (DR), or arterial hypertensive retinopathy (AHR) was used. The RGC were labeled by introducing crystals of the fluorescent carbocyanine dye DiI into the nerve fiber layer, which contains ganglion cell axons. Results The typical silhouettes of both major types of RGC, parasol and midget cells, were identified. The axons in DR and AHR retinas showed morphology changes such as irregular swelling and beading. Dendritic field sizes were significantly reduced in RGC of both the hypertonic and diabetic retinas. A significant reduction in branching frequency was evident in both the diabetic and hypertonic retinas, in both the midget and the parasol cells. In LC retinas, both parasol and midget RGC were observed within the LC spots, although their numbers were dramatically decreased compared with normal retinas. Conclusions The data suggest that diabetes and arterial hypertonia have similar effects on the morphology of RGC, in addition to causing microvascular alterations and bleeding. Therefore, therapeutic measures and prognostic outcomes in diabetic and hypertensive retinopathy should also consider regressive changes in retinal neurons.     

Paraneoplastic retinopathy associated with occult bladder cancer

The aim was to report the first case of cancer-associated retinopathy (CAR) presenting before bladder cancer diagnosis. A 71-year-old woman with a history of bilateral vision loss underwent subsequent complete ophthalmic examination include a fluorescein angiography, full-field electroretinogram (ERG), serology including serum antibodies for CAR, and positron emission tomography-computed tomography (PET-CT) scan. The patient was diagnosed with bladder carcinoma revealed by PET-CT. Timely recognition of this entity may be crucial for an increased patient survival thus adult onset progressive photoreceptor dysfunction, confirmed by ERG, should alert to a possible remote effect of known or occult malignancy. In the latter, PET-CT may be exploited as a powerful diagnostic tool.     

糖尿病视网膜病变的诊断和治疗:2016-2018年最新研究进展

糖尿病视网膜病变（diabetic retinopathy,DR）是糖尿病的一种威胁视力的并发症,是致盲的主要原因。DR发病机制复杂,目前尚不明确。大量的证据使人们意识到DR不仅是一种血管疾病,而且是一种神经退行性疾病。目前针对DR治疗方案效果有限,DR的早期诊断、防治至关重要。本文就近两年DR的诊断、治疗的最新研究进展及新的治疗靶点进行综述。     

糖尿病视网膜病变粘附分子表达与白细胞粘附的干预性研究进展

糖尿病视网膜病变是糖尿病的重要微血管并发症之一,其发病机制复杂,尚未完全阐明。近年来研究发现白细胞和粘附分子在糖尿病性视网膜病变的病理发生过程中起重要作用。本研究就糖尿病时白细胞和粘附分子表达异常、对视网膜的损害及干预性药物治疗等方面进行了综述。     

Medical management of diabetic retinopathy: fenofibrate and ACCORD Eye studies

The approach of all ophthalmologists, diabetologists and general practitioners seeing patients with diabetic retinopathy should be that good control of blood glucose, blood pressure and plasma lipids are all essential components of modern medical management. The more recent data on the use of fenofibrate in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye studies is reviewed. In FIELD, fenofibrate (200 mg/day) reduced the requirements for laser therapy and prevented disease progression in patients with pre-existing diabetic retinopathy. In ACCORD Eye, fenofibrate (160 mg daily) with simvastatin resulted in a 40% reduction in the odds of retinopathy progressing over 4 years, compared with simvastatin alone. This occurred with an increase in HDL-cholesterol and a decrease in the serum triglyceride level in the fenofibrate group, as compared with the placebo group, and was independent of glycaemic control. We believe fenofibrate is effective in preventing progression of established diabetic retinopathy in type 2 diabetes and should be considered for patients with pre-proliferative diabetic retinopathy and/or diabetic maculopathy, particularly in those with macular oedema requiring laser.     

Necrotising herpetic retinopathies: a review and progressive outer retinal necrosis case report

Necrotising retinopathies can be visually devastating. Most often associated with the viral family Herpesviridae and seen in both immune‐competent and immunocompromised hosts, possible complications of necrotising retinopathies include progressive retinal necrosis with or without macular involvement, optic neuropathy and ultimately, secondary retinal detachment. Examples include progressive outer retinal necrosis, acute retinal necrosis and cytomegaloviral retinitis. If diagnosed early and treated aggressively, visual complications can be prevented; however, there is no current consensus on the most appropriate antiviral regimen for each of the different varieties of necrotising herpetic retinopathy. This paper reviews aspects of varieties of necrotising herpetic retinopathy, including pathophysiology, treatment and diagnostic testing.     

生长抑素类似物在增殖性玻璃体视网膜疾病中的应用及研究进展

增殖性玻璃体视网膜疾病是全世界范围内引起视力丧失的最主要原因之一 ,目前已认可的治疗方法包括全视网膜光凝和冷冻疗法 ,这些治疗方法对视网膜会造成一定的损害。视网膜疾病尤其是增殖性糖尿病视网膜疾病的药物治疗学方面的研究如合成的生长抑素类似物的应用是一个有前景的研究领域。目前已试用长效生长抑素类似物治疗糖尿病性视网膜疾病 ,这种治疗方法是否对视网膜新生血管性疾病如早产儿视网膜疾病、老年性黄斑病变等有效 ,仍需要进一步研究。我们就生长抑素的研究概况、生长抑素受体在眼组织上的表达分布以及其在眼新生血管及增生性疾病中的应用作一综述     

外泌体在糖尿病视网膜病变的机制研究进展

外泌体是广泛存在于人体，由机体细胞产生并分泌的纳米级细胞外囊泡，能相对稳定地存在于各种生物组织和体液中，并携带特定的miRNA、蛋白质、转录因子等多种信息分子，参与调控体内多种疾病的病理生理过程。近年来随着外泌体在各学科研究的不断深入，其在眼科学领域的研究也迅速开展，目前发现外泌体在糖尿病视网膜病变、年龄相关性黄斑变性、自身免疫性葡萄膜炎、角膜病及青光眼等多种疾病中发挥重要作用。随着生活水平的提高，全世界糖尿病视网膜病变致盲人数逐年增加，而糖尿病视网膜病变机制研究未明，近年许多研究发现外泌体在其中发挥着重要作用，本文对外泌体在糖尿病视网膜病变的发生、发展机制的最新研究进展进行综述。     

Journal watch

We report a case of anti-40kDa protein autoimmune retinopathy developing 9 years after thymoma excision on a background of Good Syndrome-associated cytomegalovirus (CMV) retinitis that suggests a separate pathogenetic pathway from that of previously reported thymoma-associated autoimmune retinopathies.