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.     

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.     

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.     

Síndrome paraneoplásico ocular: retinopatía asociada al cáncer

Case ReportWe review a patient with ocular manifestations of a paraneoplastic syndrome. It was a cancer-associated retinopathy (CAR) in a woman with visual loss, and attenuated and sheathed retinal arterioles. The electroretinography (ERG) showed severe abnormalities of the a and b-waves. The tumour process was not discovered until 6 months later, when a squamous neoplasia that invaded the uterus and vagina was observed.DiscussionParaneoplastic syndromes are a group of manifestations produced as a remote effect of cancer cells. CAR syndrome is caused by autoimmune reactions to retinal antigens induced by aberrant expression of recoverin in cancer tissues. Ophthalmologists must be aware of ocular paraneoplastic signs as they can be the first manifestations of a malignant tumour.     

Carcinoma-associated retinopathy: a review with clinical examples

Cancer-associated retinopathy (CAR) is a rare paraneoplastic syndrome. In this survey we report about two further patients with CAR, who were referred to the University Eye Hospital of Tuebingen within a few months. The most common primary tumor associated with CAR is small cell carcinoma of the lung. Case reports about rhabdomyosarcoma, carcinoma of the endometrium, prostate and mamma were also described. The exact pathogenesis of CAR is still unknown. Specific autoantibodies were found against the photoreceptor protein recovering (23-kd retinal CAR antigen). However, this reaction is not present in all patients, and probably other antigens are also involved. Most of the patients experience symptoms of CAR before the primary tumor is detected. Besides glare sensitivity and flashing lights, a rapidly progressive, often asymmetric visual loss may occur. Although paracentral and mid-peripheral scotomas can be found frequently, visual field defects are often quite heterogeneous. Typically, the responses in the electroretinogram (ERG) are markedly reduced, but normal ERGs were also described. The fundus picture in CAR shows sheathing of the retinal vessels, narrowing of the arterioles and clumbing of the retinal pigment epithelium. The prognosis is poor. Frequently there is progression to bilateral loss of vision within a few months. Treatment of the primary tumor does not seem to alter the ocular prognosis. Systemic corticosteroids may be helpful in some patients. Nevertheless, no proven therapeutic regimen is currently available.     

Ocular manifestations of cancer.

Cancer may affect the eye and orbit by a direct effect of metastatic neoplastic infiltration or compression or by circulating antibodies involving paraneoplastic retinal degeneration. Metastatic tumor to the uvea is the most common form of an intraocular malignant process. The choroid is the most common site for uveal metastasis; metastases to the ciliary body, iris, retina, optic disc, 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 but the systemic prognosis is poor. The visual paraneoplastic syndromes encompass several distinct clinical and pathologic entities including carcinoma-associated retinopathy, melanoma-associated retinopathy, and bilateral diffuse melanocytic uveal proliferation. The first affects photoreceptors, the second is thought to affect bipolar cell function, and the third targets the uveal tract. Identification of circulating antibodies against retinal proteins (recoverin, 23-kD retinal protein; 46-kD and 60-kD retinal proteins) serves to recognize the paraneoplastic nature of the patient's symptoms, which frequently develop before the cancer is diagnosed. No therapy exists to stop the inexorable progressive loss of vision. Metastasis to the eye and orbit and paraneoplastic disorders represent a very bad prognostic sign. Recognition of their visual symptoms and ocular findings should alert the ophthalmologist to the possibility of cancer and systemic evaluation should be pursued.     

Choroidal neovascularization associated with cancer‐associated retinopathy

Purpose: To report an unusual association between cancer‐associated retinopathy (CAR) associated with invasive thymoma and choriodal neovascularization (CNV), treated by photodynamic theraphy (PDT). Methods: A 39‐year‐old man affected with thymoma and paraneoplastic syndrome (myasthenia gravis and diarrhoea) was observed between October 1997 and September 2007. The patient developed progressive visual dysfunction including bilateral visual acuity loss and concentric constriction of visual fields. Ophthalmological, immunological and systemic examinations were performed. Immunological evaluations included an assessment of antibody activity by indirect immunohistochemistry on sectioned rhesus monkey eye, and Western blot reactions upon an extract of pig retina. Results: Fundus ophthalmoscopy and fluorescein angiography revealed retinal vessel attenuation and retinal pigment epithelium degeneration. Electroretinogram suggested both rod and cone dysfunction. Indirect immunohistochemistry identified antibody activity within the photoreceptor outer segments. Western blots on the retina revealed that most of the patient’s antibody activity was focused upon a retinal protein antigen approximating 145 kD. These findings share the commonalities of size and retinal distribution of the interphotoreceptor retinoid‐binding protein (IRBP), a recognized autoantigen. The surgically resected mediastinal tumour was diagnosed as invasive thymoma. No other malignancy has since been found throughout nearly 10 years of follow‐up. In March 2006, the patient developed a subfoveal CNV in his left eye, which was treated by PDT. Conclusion: We describe the third case of paraneoplastic retinopathy associated with invasive thymoma. This is the first example of CAR involving autoantibodies reactive with a retinal protein having the characteristics of the IRBP, and is also the first complicated by CNV treated by PDT.     

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.     

Lymphoma-associated retinopathy

OBJECTIVE: To describe the clinical, electrophysiologic, and serologic findings in a patient with retinal degeneration associated with Hodgkin's lymphoma. DESIGN: Case report with ancillary immunohistochemical studies. METHODS: A 24-year-old woman experienced night blindness and fundus abnormalities 1 week after initiation of chemotherapy for Hodgkin's lymphoma. Visual fields and full-field electroretinograms (ERGs) were monitored over a 10-year period. Serum antibodies were studied on Western blot reactions on a solubilized extract of bovine retina. Serum antibodies were also evaluated through indirect immunohistochemistry on rhesus monkey retina. RESULTS: Visual field and ERG amplitudes, initially abnormal, became reduced further over 10 years. Serum antibodies were identified that reacted to a retinal protein or proteins approximating 65 kd; these antibodies showed immunologic activity against photoreceptors. CONCLUSIONS: A progressive paraneoplastic retinopathy can occur in association with Hodgkin's lymphoma. The pathogenesis of the retinal degeneration appears to be related to a serum antibody that is reacting to a retinal protein or proteins of approximately 65 kd.     

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.     

Paraneoplastic vitelliform retinopathy associated with cutaneous or uveal melanoma and metastases

PURPOSE: To report unusual vitelliform fundus findings in three cases of paraneoplastic retinopathy associated with metastasised cutaneous or uveal melanoma and in one case, a unique immunoreactivity response. PATIENTS AND METHODS: Observational case series. The histories of three patients with MAR-like paraneoplastic retinopathy were reviewed. Electroretinography, Goldmann perimetry, fluorescein angiography, and in one case optical coherence tomography, immunohistochemistry and Western blotting were performed. RESULTS: All patients revealed similar paraneoplastic vitelliform retinal abnormalities. Symptoms in two cases differed from the classical MAR syndrome. In one case, western blotting and immunohistochemistry demonstrated antibodies against 120-kDa, a soluble photoreceptor protein. No immunoreactivity to retinal bipolar cells was detected. CONCLUSION: The clinical, electrophysiological, and immunological findings in our patients suggest a melanoma associated paraneoplastic origin, like in MAR syndrome. However contrary to MAR syndrome, this paraneoplastic vitelliform retinopathy exhibits a peculiar fundus picture, consisting of serous macular detachment and nummular vitelliform lesions in the posterior pole. This could be an unusual presentation of MAR or a separate paraneoplastic entity.     

The cancer-associated retinopathy antigen is a recoverin-like protein.

Cancer-associated retinopathy (CAR) is a rare form of retinal degeneration that occurs in association with certain forms of cancer. CAR patients typically possess high titers of autoantibodies against a specific photoreceptor protein--the 23 kD retinal CAR antigen. The mechanisms involved in the vision loss experienced by CAR patients are not understood, but serologic studies indicate the process could include a series of autoimmune reactions directed at specific components of the retina. Because the retinal CAR antigen is the principal ocular autoantigen involved in the antibody response of CAR patients, characterizing it would contribute to the understanding of putative autoimmune involvement. Serum antibodies from CAR patients have been used to isolate the gene encoding the CAR antigen from a cDNA library of human retina. Nucleotide sequence analysis suggests that the CAR antigen shows approximately 90% homology to the published amino acid sequence of bovine recoverin.     

Cancer-associated retinopathy presenting as retinal vasculitis with a negative ERG suggestive of on-bipolar cell pathway dysfunction

A 62-year-old female patient presented to our clinic complaining of a 2 month history of shimmering photopsias and floaters. An ocular examination, fluorescein angiography, and electrophysiological testing were obtained that suggested either an inflammatory retinal vasculitis or a paraneoplastic syndrome. Melanoma-associated retinopathy was highly suspected despite the absence of previous history for cutaneous melanoma since an electronegative scotopic ERG was recorded on standard flash electroretinography. Additional investigations revealed the presence of a primary breast tumor with secondary lung and pancreatic metastasis that led to the diagnosis of cancer-associated retinopathy. The patient received chemotherapy and 4 months after the initial presentation her visual complaints but also her retinal function showed marked improvement. Cancer-associated retinopathy needs to be considered in patients presenting with retinal vasculitis and electrophysiological testing can tailor the approach in these cases.     

Ocular manifestations of various systemic disorders

Diode laser photoablation of the retinal periphery is an effective treatment for zone 1 or 2 threshold retinopathy of prematurity. Patients with small cell carcinoma of the lung and cancer-associated retinopathy have immunoreactivity with the 23-kD retinal cancer-associated antigen and a similar antigen is secreted by in vitro propagated cultures of small cell carcinoma of the lung. This cancer-associated autoimmune retinopathy is characterized by rapid visual loss, night blindness, color loss, and reduced electroretinograms. Angioid streaks start as narrow, short discontinuous hypopigmented streaks that enlarge and widen with the end stage being disciform macular degeneration, helicoid peripapillary atrophy, or diffuse choroidal sclerosis. In the setting of neonatal cholestasis, the findings of microcornea, posterior embryotoxon, mosaic iris stromal hypoplasia, anomalous optic discs, and regional peripapillary retinal depigmentation suggest the diagnosis of Alagille syndrome (arteriohepatic dysplasia).     

Selective immunohistochemical staining in the paraneoplastic retinopathy syndrome.

BACKGROUND: The mechanism leading to visual loss in paraneoplastic retinopathy is not known. An autoimmune process has been imputed based on immunologic investigations of several patients and by analogy to certain other paraneoplastic syndromes. METHODS: Two patients with documented small cell carcinoma of the lung who had clinical evidence of paraneoplastic retinopathy are described. Histopathologic examination of the retina from one patient and immunohistochemical staining of human retina with serum from control subjects and both patients were performed. RESULTS: Electroretinograms demonstrated dysfunction of photoreceptors in both patients, with predominant loss of rod function in one patient. Post mortem examination showed patchy loss of photoreceptors of the extramacular retina and relative sparing of cones, findings consistent with the clinical and electrophysiologic test results. Serum from both patients stained the retina in an identical manner, with restriction of the stain to the outer retina. Stain was present over the outer plexiform layer, the outer nuclear layer, and the inner and outer segments of most photoreceptors. A sharp demarcation was present between those areas that did and did not stain. All rod inner and outer segments appeared to stain, and many cone inner segments were not stained. Immunologic tests obtained elsewhere did not show serum antibody to the 23 kD protein. CONCLUSION: These findings support the concept of an autoimmune pathogenesis by showing selectivity of the immune response and correlation between the apparent target of the immune response and the clinical and pathologic findings. The mechanism by which cell loss occurs in the retina is not answered by this study. The absence of antibody to the 23 kD protein does not exclude the diagnosis of paraneoplastic retinopathy.     

Cutaneous melanoma-associated paraneoplastic retinopathy: histopathologic observations.

PURPOSE: To describe the retinal histopathology of paraneoplastic retinopathy associated with cutaneous melanoma. METHODS: A 59-year-old man had visual loss attributable to paraneoplastic retinopathy and died of metastatic cutaneous melanoma. His eyes were studied by conventional histopathologic techniques. RESULTS: Histopathologic examination of both eyes disclosed a marked reduction in the density of bipolar neurons in the inner nuclear layer; photoreceptor cell neurons in the outer nuclear layer were normal. Ganglion cells were present, although many showed evidence of transsynaptic atrophy. CONCLUSION: The histopathologic changes observed are consistent with clinical, immunologic, and electrophysiologic data that implicate the bipolar cell as the major site of the paraneoplastic process in cutaneous melanoma-associated retinopathy.     

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.     

Electrophysiological findings in paraneoplastic retinopathy

Paraneoplastic retinopathy is a cancer-related non-metastatic retinopathy mainly associated with lung cancer. We examined two patients with presumed paraneoplastic retinopathy, both ophthalmologically and electrophysiologically. Both patients presented with initial visual complaints of moderate reduction of visual acuity. No specific fundus anomaly was found in the fundus except for a mild attenuation of the retinal arteries. The electroretinogram and pattern reversal visual evoked responses were either markedly reduced in amplitude or non-recordable. The electrooculogram recorded in one patient demonstrated a markedly reduced light peak/dark trough ratio. These results indicate the presence of a severe and diffuse bilateral retinal dysfunction, despite the relatively good visual acuities and mild fundus changes. Electrophysiological evaluations play an important role in the diagnosis of paraneoplastic retinopathy.