Cancer-associated Retinopathy Syndrome Research Articles

Autoimmune basal ganglia encephalitis associated with anti-recoverin antibodies: A case report

Autoimmune basal ganglia encephalitis causes neurological symptoms such as parkinsonism associated with basal ganglia lesions. Here, we report a case of autoimmune basal ganglia encephalitis without retinal lesions or malignancy harboring anti-recoverin antibodies. The patient was a 67-year-old Japanese woman who developed anorexia, parkinsonism, and disturbance of consciousness 7 days before admission. Brain magnetic resonance imaging showed hyperintense bilateral basal ganglia lesions on fluid-attenuated inversion recovery images. 18F-fluorodeoxyglucose-positron emission tomography showed no malignancy in the trunk, and dopamine transporter single-photon emission computed tomography with dopamine transporters revealed reduced radiotracer uptake in the basal ganglia. Further, anti-recoverin IgG antibodies were detected in serum immunoblot. Based on the clinical and imaging findings, the patient was diagnosed with autoimmune basal ganglia encephalitis with anti-recoverin antibodies and administered high-dose immunoglobulins (HD-IVIG), which led to an improvement in clinical symptoms. Anti-recoverin antibodies are paraneoplastic antibodies that explicitly bind to Ca2+-binding proteins in the retina and cause retinopathy. This pathological sequence is defined as cancer-associated retinopathy (CAR). However, in our case, autoimmune basal ganglia encephalitis developed without CAR syndrome or malignancy. Clinicians should be aware of the possibility of autoimmune basal ganglia encephalitis showing anti-recoverin antibodies but no CAR syndrome or malignancy, which should be treated with HD-IVIG therapy.

Cancer Associated Retinopathy in Non-Hodgkin’s Lymphoma

Cancer-associated retinopathy (CAR) is an uncommon paraneoplastic retinopathy usually associated with small cell lung carcinoma. To our knowledge, there is no previous report in the English literature of CAR syndrome occurring in lymphoma patients. We describe a rare case of CAR syndrome in a 62-year-old male with non-Hodgkin’s lymphoma (NHL) treated with four doses of intravenous immunoglobulin.

Ocular paraneoplastic syndrome: Cancer-associated retinopathy

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 tumor 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 tumor.

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.

Autoantibodies against the Ca2+-binding protein recoverin in blood sera of patients with various oncological diseases

In cancer, the retinal Ca(2+)-binding protein recoverin is a paraneoplastic antigen, the aberrant expression of which is capable of triggering the appearance of specific autoantibodies in the serum of patients with malignant tumors and the subsequent development of a paraneoplastic syndrome, cancer-associated retinopathy (CAR). The frequency of serum autoantibodies against recoverin (AAR), earlier determined at a rate of 15-20% in lung cancer, is much higher than the frequency of CAR syndrome, which is approximately 1%. In the present study, we estimated for the first time the frequencies of serum AAR in patients with various types of malignancies other than lung cancer. Patient biospecimens were collected to analyze for the presence of AAR. Additionally, various cell lines were cultivated and analyses were performed using Western blotting and RT-PCR. Results showed that in all cases tested, the AAR frequencies did not exceed 10%. Five AAR-positive patients with various types of cancer were available for ophthalmological investigation and only one of these patients had CAR syndrome. This result is consistent with the conclusion made in our previous studies of lung cancer that serum AAR do not necessarily trigger the development of CAR syndrome.

Cancer-Associated Retinopathy in Non-Hodgkin Lymphoma: The Challenge of Treatment

Abstract Introduction Cancer-associated retinopathy (CAR) syndrome is rare paraneoplastic visual syndrome, usually associated with small-cell lung carcinoma. We report, to our knowledge, the first case in the English-language literature of CAR syndrome occurring in a patient with non-Hodgkin lymphoma (NHL) treated with intravenous immunoglobulin (IVIG). Case Report A 62-year-old male was diagnosed with stage IV B-cell follicular NHL treated with 6 cycles of R-CHOP (rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone). Five weeks after the last cycle, he presented with progressive decrease of vision in both eyes, flickering lights, and night blindness. On examination, corrected visual acuity was 20/80 and 20/100 in the right and left eye, respectively, and color vision was diminished bilaterally. Fundus examination revealed pallor of the optic disks while visual field examination showed profound field constriction. A multifocal electroretinogram revealed dysfunction of both rods and cones characteristic of diffuse photoreceptor degeneration that is supporting the diagnosis of CAR syndrome. Magnetic resonance imaging of the head and orbits showed no signs of metastases or other abnormalities. Western blot analysis of the patient's serum showed a positive antibody reaction with 23-kD component coinciding with the molecular mass of human recoverin. The patient was started on oral prednisone 60 mg daily. Three weeks later he still complained of decreased vision in both eyes. IVIG (400 mg/kg/day) was given for 4 doses. Following the second dose, the patient showed signs of improvement. Four weeks after finishing the full treatment, visual acuity improved to 20/40 in both the right and left eye, with no relapse during the 8-month follow-up period. Discussion To our knowledge, there has been only 1 previous report (in the French-language literature) of CAR syndrome in lymphoma patients. Matus et al described 2 NHL patients with symptoms of CAR, which was confirmed by the presence of anti-recoverin antibodies. Both cases were treated by corticosteroids with only minimal response. Since CAR syndrome is a rare condition, no specific treatment has been shown to be effective. Treating the underlining malignancy has not been shown to result in better visual outcomes, and immunosuppression with oral or intravenous corticosteroid exhibits only a transient or undetectable response. Furthermore, plasmapheresis has not been effective. Conclusion CAR may occur in NHL. IVIG may be an effective option for treating these patients, especially if started early enough before permanent retinal damage occurs.

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.

A Case of Cancer Associated Retinopathy with Small Cell Lung Carcinoma

Cancer associated retinopathy (CAR) syndrome is a very rare ocu lar manifestation of paraneoplastic syndrome, and is characterized clinically by progressive visual impairment. Immu ne cross-reactivity between antigens in the cancerous tissue and antigens in the retina may play an important role in its pathogenesis, and most of cases are associated with lung carcinoma, particularly small cell lung cancer. The clinical triad of CAR is described as photosensitivity, ring scotomata, and an attenuated retinal arterial caliber.Here, we report a 61-year old male patient with CAR syndrome, w ho had small cell lung carcinoma in the stage of limited disease, with a brief review of the relevant literature .(Tuberc Respir Dis 2005; 59: 679-683)Key words : Cancer associated retinopathy, CAR syndrome, Paraneoplastic syndrome, Small cell lung cancerAddress for correspondence : Kwak Jinyoung M.D.,Department of internal medicine, Presbyterian medical center, Junghwasandong, Wansangu, Jeonju, Jeonlabukdo, KoreaPhone : 063)230-8919 Fax : 063)230-8917E-mail : drnbear@gmail.comReceived: Oct. 4. 2005Accepted: Oct. 24. 2005

Anti-apoptotic effects of CNTF gene transfer on photoreceptor degeneration in experimental antibody-induced retinopathy

Autoantibodies against recoverin are found in the sera of patients with cancer-associated retinopathy syndrome, a paraneoplastic disease associated with retinal degeneration. We have previously shown that anti-recoverin autoantibodies induced photoreceptor apoptotic cell death after injection into the vitreous of Lewis rats. Ciliary neurotrophic factor (CNTF) has been shown to promote the survival of a number of neuronal cell types, including photoreceptors. In this study, we examined whether an adeno-associated virus (AAV)-mediated delivery of gene encoding the human CNTF protected photoreceptor cells from anti-recoverin antibody-induced death. One month after subretinal injection of the AAV–CNTF gene into one eye and a control vector into the other eye, an anti-recoverin antibody was injected to induce retinal cell death in Lewis rats. Subretinal administration of the virus led to an efficient transduction of photoreceptors, as indicated by immunostaining of retinas with anti-CNTF. Histological examination of the corresponding retinas showed that photoreceptor cells were significantly protected from apoptotic death in the CNTF-treated eyes. CNTF treatment of the retinas resulted in a time-dependent activation of STAT 3. The present study shows that an AAV-mediated delivery of CNTF may protect photoreceptors from antibody-induced cell death through the activation of STAT3 and the suppression of caspase 3 activity, a key caspase leading to apoptosis. Thus, CNTF may be a useful treatment for human antibody-mediated retinal degeneration.

Mechanism of CAR syndrome: anti-recoverin antibodies are the inducers of retinal cell apoptotic death via the caspase 9- and caspase 3-dependent pathway

Anti-recoverin autoantibodies have been associated with cancer-associated retinopathy (CAR), a paraneoplastic blinding disease. Those antibodies have been shown to induce apoptotic death of photoreceptor cells. The objective was to ascertain the mechanisms of retinal death induced by anti-recoverin antibody in vitro by examining the apoptotic pathway involved in retinal cell death. Internalization of anti-recoverin antibody or its Fab fragments by retinal cells mediated by endocytosis lead to cytotoxicity. Antibody cellular translocation induced the increase of bcl-x s and bax and the decrease in the bcl-x L protein. We detected the release of cytochrome c and down-regulation of the apaf-1 protein. This correlated with the sequential activation of caspase 9 and caspase 3, as well as the degradation of the caspase substrate PARP and the fragmentation of DNA. Our data show that anti-recoverin antibodies are inducers of apoptosis through the mitochondrial pathway involving caspases 9 and 3. We propose that a similar mechanism may be in place in patients with CAR syndrome where high levels of circulating antibodies have been associated with retinal degeneration.

Low titre autoantibodies against recoverin in sera of patients with small cell lung cancer but without a loss of vision

To date, many authors have described the presence of autoantibodies against various neuronal proteins, paraneoplastic antigens (PNA), in a serum of patients with different kinds of malignant tumors located outside the nervous system. These autoantibodies may cross-react with the corresponding PNA or their epitops present in neurons and thus initiate the development of a variety of neurological disorders, paraneoplastic syndromes (PNS), even though the primary tumor and its metastases have not invaded the nervous system. Cancer-associated retinopathy (CAR) is a rare ocular PNS induced by autoantibodies against several retinal antigens, one of which is a photoreceptor calcium-binding protein, recoverin. Only several CAR patients with a few kinds of cancer (endothelial carcinoma, breast cancer, epithelial ovarian carcinoma) have so far been found to contain autoantibodies against recoverin in their sera. As for lung cancer, the majority of CAR cases mediated by anti-recoverin autoantibodies have been revealed in patients with the most malignant lung cancer, small cell lung carcinoma (SCLC), and only one similar case has been described for a patient with non-small lung carcinoma. The common feature of all these anti-recoverin-positive patients, irrespective of the type of cancer, is the presence of both the CAR syndrome and high titres (as a rule, more than 1:1000) of the underlying autoantibodies in their serum. In this study, we have used recombinant myristoylated recoverin to screen serum samples of 50 patients with SCLC by Western blot and revealed 5 individuals with low titres of anti-recoverin antibodies, who have no manifestation of a loss of vision. To our knowledge, this is the first report on the presence of low titre autoantibodies against recoverin in a serum of patients with cancer, but without visual dysfunction.

Autoimmune retinopathy: patients with antirecoverin immunoreactivity and panretinal degeneration.

To investigate whether antirecoverin antibodies are present in patients with retinitis pigmentosa (RP). Recoverin, a retinal protein, has been implicated as a cause of cancer-associated retinopathy (CAR), which manifests as an RP-like retinal degeneration. The rationale is that the ocular findings in CAR syndrome are similar to those found in many forms of RP, and since 40% of patients with RP have no family history, some patients may have an underlying autoimmune process causing or contributing to their retinopathy. Serum samples from 521 patients diagnosed with RP were screened for antiretinal proteins activity by Western blot analysis. Fifty-one patients had antibody reactivity against retinal proteins in the range of 23 to 26 kd and underwent dot-blot analysis for antirecoverin antibody, checking IgG and IgM antibodies. Enzyme-linked immunosorbent assay (ELISA) was performed to evaluate the titer of antirecoverin antibodies in patients with positive results on dot-blot analysis. Lymphocyte proliferation assays using recoverin were performed on 26 samples. Ten patients were found to have antirecoverin antibody and/or cellular immunoreactivity. Eight patients had positive dot-blot testing: 6 patients had both IgG and IgM antirecoverin activity, and 1 patient each had IgG or IgM activity. In these 8 patients, numerous other antiretinal protein antibodies were present. Three patients had positive recoverin-mediated lymphocyte proliferation, and all patients were positive for antirecoverin antibodies on ELISA testing. Antirecoverin immunoreactivity was found in 10 patients without systemic malignancy but with clinical findings consistent with RP. These results suggest that there are other immunogenic mechanisms occurring in the formation of antirecoverin antibodies in addition to the putative tumor-mediated mechanisms. This survey suggests that there may be rare cases of CAR-like syndrome in the category of simplex RP, or that some patients with RP also have antirecoverin antibodies that may be exacerbating their underlying disease. Arch Ophthalmol. 2000;118:1525-1533

Anti-Enolase-α Autoantibodies in Cancer-Associated Retinopathy: Epitope Mapping and Cytotoxicity on Retinal Cells

Patients with cancer-associated retinopathy syndrome (CAR), a progressive blinding disease related to retinal degeneration and systemic tumor outside the eye, develop autoantibodies against α-enolase. A small percentage of healthy subjects without evident tumor or visual symptoms also possess autoantibody against enolase. In these studies we examined the fine specificity of anti-enolase antibodies derived from patients with CAR and healthy individuals, using synthetic peptides covering the entire sequence of human α-enolase. Epitope mapping revealed that three binding regions of enolase within the residues 31–38 (FRAAVPSG), 176–183 (ANFREAMR), and 421–428 (AKFAGRNF) were common for all autoantibodies tested. However, pathogenic sera recognized an additional unique region, the sequence 56–63 (RYMGKGVS). There were also differences inin vitrocytotoxic activities on E1A.NR3 retinal cells and cell-death promoting activities between anti-enolase antibodies of healthy and CAR affected individuals. These studies showed that anti-enolase antibodies from patients with CAR were able to induce apoptotic cell death in E1A.NR3 retinal cells and provided a potential mechanism for retinal degeneration in humans.

Paraneoplastic Retinopathy

We present the case of a 74-year-old man with rapidly progressive bilateral visual loss, optic disc pallor, retinal arteriolar attenuation, and an abnormal electroretinogram with a 90% reduction in cone function and a 50% reduction in rod function. He was examined for a suspected cancer-associated retinopathy (CAR). Although he was found not to have expressed the previously reported 23-kd CAR antibody, high titers were found of an antibody to a 60-kd retinal protein, which as yet remains unidentified. An initial clinical search for an underlying cancer was unsuccessful, but 2 months later a mediastinal mass was found on chest x-rays, and biopsy confirmed a diagnosis of small-cell lung carcinoma. Combined therapy with oral corticosteroids and plasmapheresis resulted in a recovery of vision from counting fingers to 20/200 in the right eye and 20/40 to 20/25 in the left eye. Conventional chemotherapeutic management of the small-cell lung carcinoma was instituted, and the modest visual recovery was maintained. The visual improvement as well as lung tumor regression were accompanied by a decline in antibody titers from 1:2,000 pretreatment to 1:200 during the course of therapy. The absence of reactivity with the previously described 23-kd retinal antigen of the CAR syndrome does not exclude the diagnosis of paraneoplastic retinopathy in patients fitting the clinical profile of this disease.

The Occurrence of Serum Autoantibodies against Enolase in Cancer-Associated Retinopathy

Cancer-associated retinopathy (CAR) is an uncommon paraneoplastic disease in which degeneration of the retina occurs as a remote effect of cancer in a distant part of the body. Immunoreactivity of sera from CAR patients and controls have been analyzed. Immunostaining of human retinal proteins showed that a soluble protein ofMr∼46 kDa (p46) is labeled by antibodies from several CAR patients with various types of cancer (lung, breast, bladder, prostate, salivary gland, and gastrointestinal tract cancer and chronic lymphocytic leukemia). These sera didnotshow reactivity with the 23-kDa protein previously associated with CAR. To identify and further characterize p46, the retinal protein was purified to homogeneity by anion-exchange chromatography and preparative gel electrophoresis. Protein sequence analysis of the peptides from p46 revealed a high homology with human enolase, an important glycolytic enzyme. Although enolase has been previously identified as a product of several types of tumors, and enolase activity has been detected in the sera of some cancer patients, the existence of autoantibodies directed to enolase has not been described. This is the first report of the presence of serum antibodies to retinal enolase in the patients with cancer and the CAR syndrome. When antibodies of specific isotypes (IgG, IgM, and IgA) were measured, IgG1 isotype was dominant. The significance of these antibodies for the disease process is under investigation.