肿瘤相关性视网膜病变的研究进展

肿瘤相关性视网膜病变(cancer-associated retinopathy,CAR)是一种与肿瘤有关的视网膜变性疾病,其发病机制认为是肿瘤抗原诱导机体产生抗视网膜蛋白的抗体而引起的自身免疫性疾病,而非眼部原发肿瘤的占位压迫或全身其他部位肿瘤转移所引起.CAR对视功能的影响很大,目前该病已逐渐被眼科医师所认识.本文从CAR的发病机制、临床表现、诊断及鉴别诊断、治疗方面作一综述.     

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。     

自身免疫性视网膜病变小鼠模型的建立及评价

目的 诱导自身免疫性视网膜病变（AIR）小鼠模型,对其发生过程、病理及功能特征进行评价。设计 实验研究。 研究对象 18只7~9周鼠龄C57BL/6J小鼠用于诱导AIR发生;同龄同种小鼠6只设立为对照组。方法 用完全弗氏佐剂（CFA）乳化的小鼠重组恢复蛋白（recoverin）（CFA-recoverin）免疫小鼠作为诱导组,用CFA-PBS注射小鼠作为对照组。在免疫后的第0天和第2天注射百日咳毒素（PTX）破坏血-视网膜屏障。利用蛋白印迹法分析、 多模态影像检测及组织病理学方法评价造模指标。主要指标 诱导后3、6、8周小鼠血清recoverin抗体的表达、裂隙灯检查、彩色眼底照相、OCT、FFA或视网膜电图（ERG）的表现及视网膜组织学染色特征。结果 诱导组小鼠在第3周出现血清recoverin抗体阳性;第6周抗体表达明显增加并开始出现双眼少量视网膜黄白色病灶,OCT示外层视网膜轻度受损;第8周视网膜浸润灶明显扩大,OCT显示外层视网膜连续性明显破坏。第8周FFA显示病灶区视网膜下明显荧光渗漏;ERG示视杆及视锥反应波振幅显著降低。第6周及第8周病理学显示不同程度外层视网膜结构破坏及炎性细胞浸润。结论 重组recoverin蛋白皮下注射可成功诱导小鼠AIR发生,其眼部表现及病理学特征与AIR患者大致相似,是进行AIR研究的良好工具。（眼科,2023,32： 142-147）     

癌症相关性视网膜病变的自身免疫机制

癌症相关性视网膜病变 (CAR)是指非眼部原发肿瘤的占位压迫或肿瘤转移所致的一种视网膜变性疾病，为机体癌症的远部效应。自身免疫在CAR发病中起重要作用。其中抗恢复蛋白抗体、抗a-烯醇化酶抗体、抗热休克蛋白抗体与CAR的相互关系引起 了较多关注。糖皮质激素疗法、血浆过滤疗法、针对恶性肿瘤的放射或化学药物治疗、免疫球蛋白、免疫调节剂等均已试用于CAR的治疗。但其确切发病机制以及有效的治疗方法仍需进一步的系统研究。（中华眼底病杂志，2004，20：267-269）     

婴幼儿患者视网膜电图测定及其临床意义

目的 了解婴幼儿患者视网膜电图测试的特点及其临床应用意义.方法 根据国际临床视觉电生理学会ERG标准化方案,应用日本光电公司生产的Neuropaek MEB-2200K电生理仪对出生40d至6周岁以下的婴幼儿患者共314例(621只眼)进行测试.结果 将314例(621只眼)患者根据临床诊断分组.各种病变出现不同比例的ERG改变,异常眼中锥杆细胞ERG异常和熄灭型最为多见,其次为视锥细胞ERG降低,杆锥细胞ERG异常也占较高比例,其他类型较少.其中视网膜病变患者以熄灭型ERG为主,其次为锥杆或杆锥细胞ERG异常,眼球震颤婴幼儿主要表现为锥杆ERG异常,其次为视锥细胞ERG下降和杆锥细胞ERG异常.约半数屈光不正患者和弱视婴幼儿ERG正常,异常者中以视锥ERG下降多见.结论 大部分婴幼儿患者的ERG出现异常.因此,继续推广视觉电生理检查的技术和相关知识对于婴幼儿眼病的正确诊断具有重要的意义.     

F-ERG和M-ERG联合检测白内障术前视功能

目的　检测白内障眼术前视网膜功能。方法　对拟行白内障摘出术眼术前分别行暗适应F ERG时域分析法和M ERG频域分析法检查 ,比较白内障合并黄斑部视网膜病变 (黄斑变性、裂孔、出血 ,中心性脉络膜视网膜病变等 )眼、白内障合并周边视网膜病变 (高度近视视网膜格子样变性、通常型视网膜色素变性等 )眼与单纯白内障眼术前F ERG最大混合反应振幅、M ERGflicker 30Hz频谱间的差异。结果　白内障合并黄斑部视网膜病变眼术前F ERG最大混合反应a、b波振幅与单纯白内障组比较差异无显著性(P >0 0 5 ) ,而M ERGflicker 30Hz频谱比较 ,1环的差异有显著性 (P <0 .0 1) ;白内障眼合并周边视网膜病变组术前F ERG最大混合反应a、b波振幅与单纯白内障组比较差异有显著性 (P <0 0 1) ,而M ERGflicker 30Hz频谱比较 ,4～ 5环的差异有显著性 (P <0 0 1)。结论　F ERG时域分析法对白内障合并周边视网膜病变有一定的诊断作用 ,而M ERG频域分析法对白内障合并黄斑部视网膜病变的检测较F ERG敏感 ,F ERG、M ERG联合检测有助于更好地评价白内障眼术前视网膜功能。     

双侧弥散性葡萄膜黑色素细胞增生症的研究现状

双侧弥散性葡萄膜黑色素细胞增生症(bilateral diffuse uveal melanocytic proliferation,BDUMP)是一种罕见的以双眼弥漫性葡萄膜增厚和良性黑色素细胞增生为主要特征的副肿瘤综合征.其发病机制尚不明确,好发于中老年人,可引起双眼视力逐渐丧失,眼底表现为多发性类圆形斑片状病灶,...     

进朽性眼外肌麻痹与良性视网膜色素沉着

通常在青年期开始发病的进行性上睑下垂与眼肌病变是进行性眼外肌麻痹的特征。本病可合并有某些全身性变性病变或营养衰竭性病变(Abiotrophies)。病例为散发性而更常见为家族性。不少病例合并有进行性的或良性的色素性视网膜病变。作者对病例进行了荧光造影、视网膜电流图(ERG)、眼电图(EOG)、脑电图(EEG)、暗适应及色觉等检查。作者报告一例17岁男性患者,双眼进行性上睑下垂4年,神经科检查拟诊为重症肌无力,但腾喜龙(Tensilon)试验阴性,且药物治疗无效。家族史无异常,亦无夜盲、视力减退或风疹病毒接触史。双眼视力均为20/20(有可略而不计的屈光不正),双侧明显上睑下垂、眼球转动受限及右眼为注视眼的外斜视,瞳孔反应灵敏。眼底有椒盐样色素性视网膜病变,视乳头及血管正常。荧光血管造影显示含眼底色素沉着浓密区与浅淡区均无荧光渗漏现象,血管无明显病变。色觉检查正常,明、暗适应的ERG波幅均降低,暗适应曲线降低但仍属于正常范围,脑电图有异常。作者在讨论中指出,进行性眼肌麻痹之色素牲视网膜病变与一般之视网膜色素变性不同,是     

封面图片说明

系统性红斑狼疮并发双眼类远达性视网膜病变。患者女性,15岁。双眼视力下降1个月。矫正视力均为0.06。眼压正常。体温38℃。双眼结膜无充血,角膜透明,房水清晰,玻璃体未见炎症细胞。眼底:双眼后极部视网膜大片棉绒斑及出血,黄斑区呈白色斑片状。血液化验:抗链O升高(141 IU/ml),抗核抗体升高(1:320),抗核抗体核型为胞核混合型,抗核糖     

急性区域性隐匿性外层视网膜病变的研究进展

急性区域性隐匿性外层视网膜病变(AZOOR)是一种少见的单眼或双眼发病的外层视网膜疾病,病因尚不明确,好发于年轻女性,近视人群发病常见。主要表现为:突发闪光感、眼前暗点、视力下降,眼底无明显异常或改变轻微。视野改变以生理盲点扩大为主,伴或不伴其他形式视野缺损,全视野视网膜电图(ERG)振幅及潜伏期异常,多焦视网膜电图表现为与视野缺损区一致的振幅降低。影像改变具有多样性,主要表现为吲哚青绿眼底血管造影(ICGA)、眼底自发荧光(FAF)、频域相干光层析成像术(SD-OCT)上涉及外层视网膜、视网膜色素上皮层、脉络膜层的典型三区带状改变和病灶边界特征性AZOOR线,后者以FAF上表现最明显。超广角成像技术的发展为周边病变区的检出提供了条件。目前认为该病具有一定的自限性,尚无统一的治疗标准。为加强对该病的认识,本文对AZOOR的概念、发病特点及临床特征、辅助检查、鉴别诊断、病因假说和治疗与预后等进行综述。     

Paraneoplastic retinopathy

Paraneoplastic retinopathy (PR) mainly includes cancer-associated retinopathy (CAR) and melanoma-associated retinopathy (MAR). Emerging evidences indicate that PR is mediated by immune cross-reaction between circulating antibodies originally generated against remote tumor with antigens expressed on retinal neurons. It is believed that CAR is a consequence of the autoantibodies against the photoreceptors and MAR is the autoantibodies against the retinal ON-bipolar cells. Recoverin autoantibody in serum is closely related to the pathogenesis of CAR, and the inactivation of TRPM1 channel plays a key role in dysfunction of ON-bipolar cells in MAR. PR is characterized by visual dysfunctions, including decreased vision, night blindness, shimmering or flickering, and abnormalities of symbolic electroretinogram appearances. Based on the history of tumors, ophthalmic symptoms, and existance of circulating antibodies, it is easy to make a diagnosis of PR. Immunosuppressants and glucocorticoids may improve the visual dysfuctions in PR subjects.     

Neuro-ophthalmological paraneoplastic syndromes: a review

Lesions involving the visual system due to the remote effect of cancer are uncommon. Their clinical manifestations are protean. The main symptoms are visual loss, caused by retinopathy or optic neuritis, and abnormal eye movements. Cancer-related retinopathy (CAR) has been primarily described in patients with small-cell lung carcinoma, and it is distinct from melanoma associated retinopathy (MAR), and the retinopathy caused by bilateral diffuse uveal melanocytic proliferation (BDUMP) observed in patients with various neoplasias. The main underlying tumours in patients with paraneoplastic optic neuritis are lung and breast carcinomas. Eye movement disorders consist of opsoclonus, associated with neuroblastoma in infants and children and various tumours in adults, and ophtalmoplegia caused by paraneoplastic myasthenia gravis or paraneoplastic brainstem encephalitis. The differential diagnosis of the neuro-ophthalmological paraneoplastic syndromes includes primarily metastatic and treatment-related lesions. In some patients the paraneoplastic nature of the ophthalmological disorder my by proven by specific serum antibodies. These antibodies are also markers of the underlying and often non-diagnosed cancer, but their pathogenic role remains unproven.     

Bilateral diffuse uveal melanocytic proliferation in a patient with cancer-associated retinopathy

PURPOSE: To describe a patient with bilateral diffuse uveal melanocytic proliferation (BDUMP) and cancer-associated retinopathy (CAR). DESIGN: Interventional case report. METHODS: A 66-year-old woman developed progressive vision loss 4 months after total hysterectomy. Ophthalmologic examination, Western blot test of sera and aqueous humor, and immunohistochemistry of carcinoma cells were performed. RESULTS: Testing revealed BDUMP and severe retinal dysfunction. Autoantibodies against recoverin and heat shock cognate protein 70 (hsc 70) were detected in serum. Cytoplasmic immunoreactivity for recoverin and hsc 70 was observed in endometrioid carcinoma cells. CONCLUSIONS: Simultaneous cases of BDUMP and CAR are rare. Aberrantly expressed recoverin and hsc 70 triggered serum autoantibody production, which caused photoreceptor degeneration.     

Ocular manifestations of cancer

Cancer may affect the eye and orbit as a direct result of metastatic neoplastic infiltration, compression, or circulating antibodies involving paraneoplastic retinal degeneration. A metastatic tumor to the uvea is the most common form of an intraocular metastatic process. The choroid is the most common site for uveal metastasis; metastases to the ciliary body, iris, retina, optic disk, and vitreous are rare. Approximately one-third of patients have no history of primary cancer at the time of ocular diagnosis. Breast and lung carcinomas for women and lung and gastrointestinal carcinomas for men most commonly metastasize to the eye and orbit. The short-term prognosis for vision is usually good after an individualized therapeutic approach (chemotherapy, hormonal therapy, external beam radiotherapy, or plaque radiotherapy), but the systemic prognosis is poor. The visual paraneoplastic syndromes encompass several distinct clinical and pathological entities including carcinoma-associated retinopathy (CAR), melanoma-associated retinopathy (MAR), and bilateral diffuse melanocytic uveal proliferation (BDUMP). The CAR syndrome affects photoreceptors, MAR is thought to affect bipolar cell function, and BDUMP targets the uveal tract. Identification of circulating antibodies against retinal proteins (recovering, 23-kDa retinal protein; 46-kDa and 60-kDa retinal proteins) serves to recognize the paraneoplastic nature of the patient's symptoms, which frequently develop before the cancer is diagnosed. Anecdotal therapeutic responses are described after systemic steroids, immunoglobulin injection, and plasmapheresis. Recognition of their visual symptoms and ocular findings should alert the ophthalmologist to the possibility of cancer and systemic evaluation should be pursued.     

Clinical and immunologic aspects of cancer-associated retinopathy

PURPOSE: To report clinical and immunologic aspects of cancer-associated retinopathy (CAR). DESIGN: Observational consecutive case series. METHODS: A retrospective review was made of 18 consecutive patients with cancer-associated retinopathy who had antiretinal antibody determination by Western blot testing. RESULTS: Clinically, a variety of ophthalmic observations including electroretinography impairment, retinal vessel narrowing, deterioration of visual acuity, visual field changes, and uveitis were frequently observed. As retinal autoantigens in the 18 cases, recoverin was found in all 18 cases (100%), heat shock cognate protein 70 (HSC70) was found in six cases (33%), and other proteins were found in four cases (20%). These antibodies were detected in only 60% of the patients at the initial examination, however, and then became increasingly apparent on the subsequent testing that was performed three times on serum samples obtained sequentially during the following months. CONCLUSION: For diagnosis of cancer-associated retinopathy, the presence of serum autoantibody toward recoverin is essentially required in addition to the characteristic clinical aspects noted above.     

Cancer-associated retinopathy induced by both anti-recoverin and anti-hsc70 antibodies in vivo

PURPOSE: In a previous study, both recoverin and heat shock cognate protein 70 (hsc 70) were found as autoantigens recognized by sera from four patients with cancer-associated retinopathy (CAR). This observation suggested that autoimmune reactions against recoverin and hsc 70 might be involved together in the pathogenesis of CAR. The purpose of the present study is to investigate the effects of these autoantibodies on retinas in vivo. METHODS: Functional and morphologic properties of the retinas were evaluated after anti-recoverin and/or anti-hsc 70 antibodies were intravitreously injected into Lewis rats' eyes. RESULTS: Responses in electroretinogram (ERG) of eyes penetrated with anti-hsc 70 antibody were comparable with the control, but those with anti-recoverin antibody were remarkably reduced during the 3-week period after the injection. Such anti-recoverin antibody-induced reduction was significantly enhanced by copenetration with anti-hsc 70 antibody. Immunofluorescence microscopy demonstrated that after intravitreal injection, anti-recoverin antibody penetrated toward the outer nuclear layer (ONL) and outer segments within 12 to 24 hours, and the presence of the antibody in the retina diminished during the next few days. Histopathology revealed significant thinning of the ONL and inner nuclear layer (INL) in the affected retina in comparison with the control. Throughout the ONL and INL, apoptotic cells were recognized by TdT-dUTP terminal nick-end labeling. The antibody-induced retinal dysfunction was effectively treated by administrations of either corticosteroid or cyclosporin A. CONCLUSIONS: These observations suggest that anti-recoverin- and anti-hsc 70 antibody-induced retinal dysfunction in Lewis rat is a good model to study the pathophysiology of CAR.     

Autoantibodies against retinal proteins in paraneoplastic and autoimmune retinopathy

Background  

Autoimmune retinal degeneration may occur in patients who present with sudden or, less commonly, subacute loss of vision of retinal origin, associated with an abnormal ERG, through the action of autoantibodies against retinal proteins. Often the patients are initially diagnosed with or suspected of having a paraneoplastic retinopathy (PR), such as cancer-associated retinopathy (CAR). However, there is limited information on the occurrence, the specificity of autoantibodies in these patients, and their association with clinical symptoms.     

A FACTOR FOUND IN THE IGG FRACTION OF SERUM OF PATIENTS WITH PARANEOPLASTIC BILATERAL DIFFUSE UVEAL MELANOCYTIC PROLIFERATION CAUSES PROLIFERATION OF CULTURED HUMAN MELANOCYTES

PURPOSE:: To determine if there is a factor in the serum of patients with bilateral diffuse uveal melanocytic proliferation (BDUMP) that causes melanocytic proliferation. METHODS:: Human melanocytes and melanoma cells were grown and exposed to serum or plasma of patients with BDUMP, other neoplastic conditions, or control media. Preliminary studies using serum were conducted in an unmasked fashion. In addition, IgG-depleted and IgG-enriched plasma was also tested in a similar fashion. Experiments using plasma were conducted triple masked. To show that the proliferation was melanocyte selective, human dermal fibroblasts, keratinocytes, and ovarian cancer cells were treated with plasma of the BDUMP cases or controls, and the effect of this exposure on their proliferation was quantified. RESULTS:: At 72 hours, the serum of BDUMP patients caused statistically significant increased proliferation of normal human melanocytes. Further studies at 6 days demonstrated similar findings. In addition, melanocytes grown in BDUMP serum exhibited a disorganized morphology with foci of multilayered cells. Cultured melanoma cells also showed statistically significant increase in growth in serum from BDUMP patients compared with controls. Masked plasma studies further confirmed these findings and showed that the IgG fraction appeared to contain the melanocyte growth-stimulating factor. The human fibroblasts, keratinocytes, and ovarian cancer cells did not show an increase in growth with the BDUMP plasma treatment. CONCLUSION:: Patients with BDUMP have a factor in the IgG fraction that selectively causes melanocyte proliferation. How it causes proliferation of human melanocytes and melanoma cells needs to be further elucidated.     

Anti-alpha-enolase antibodies in cancer-associated retinopathy with small cell carcinoma of the lung

PURPOSE: To present a case of cancer-associated retinopathy (CAR) in a patient with small cell carcinoma of the lung and antiretinal antibodies who experienced visual symptoms before diagnosis of cancer. DESIGN: Case report. METHODS: A 61-year-old man with a sudden loss of vision and photophobia was referred to the ophthalmology service. Antiretinal antibodies were determined by Western blot analysis. RESULTS: The patient was found to have small cell carcinoma of the lung without metastasis and was surgically treated. His visual loss was asymmetrical. The full field ERG was normal, even though his vision in the right eye became progressively worse. The patient was treated with methylprednisolone and showed significant improvement. Before surgery, serum tests showed antiretinal protein 35-kD; 1 week after surgery, antiretinal protein 35-kD and 46-kD (alpha-enolase); and 1 month after surgery, anti-alpha-enolase. CONCLUSIONS: Typical visual symptoms for paraneoplastic retinopathy are not always present. The absence of antirecoverin antibodies does not exclude a diagnosis of CAR.