Pancreatic neuroendocrine paraneoplastic optic neuropathy: confirmation with antibody to optic nerve and hepatic metastasis.

A 68-year-old woman presented with bilateral visual loss as the only clinical manifestation of an occult pancreatic nonsecretory neuroendocrine tumor (NET). The suspected diagnosis of paraneoplastic optic neuropathy was confirmed using immunofluorescence assays to demonstrate the presence of antibodies in the patient's serum that reacted with antigen(s) in the optic nerve and in the pancreatic NET hepatic metastasis. Treatment of the underlying cancer was followed by marked improvement in visual function.

Cone dysfunction as a paraneoplastic syndrome associated with retinal antigens approximating 40 kiloDalton.

Reports on cancer-associated retinopathies (CAR) have increased in recent years as the autoimmune reactions responsible have become better understood. The 23-kDalton autoantigen 'recoverin' was the first retinal antigen implicated in CAR, but others have since been described. We report an additional case involving an autoantigen other than recoverin, with five-year follow-up of a 50-year-old woman suffering from the CAR syndrome, with ocular abnormalities restricted to cone dysfunction. The patient had a history of laryngeal carcinoma surgically removed 18 months prior to presenting to the ophthalmologist with photophobia and decreased vision in both eyes. The patient's abnormal retinal hypersensitivity included antibody activity with two retinal antigens approximating 40 kD, located within the outer segments of the photoreceptor layer. To our knowledge, this is the first description of a cancer-associated, cone-specific dystrophy involving an abnormal amount of immunologic activity with two retinal proteins approximating 40 kD, that may prove to be isoforms of the same antigen.

Exudative Polymorphous Vitelliform Retinopathy: Importance of Early Recognition of the Condition in Patients with Metastatic Melanoma.

INTRODUCTION: Because of the advent of monoclonal antibodies in the treatment of metastatic melanoma, patients with this disease are surviving longer. Early recognition of the disease has therefore become even more important. CASE REPORT: We present a patient with vitelliform maculopathy, a paraneoplastic retinal maculopathy that is under-recognized. Clinically the retinal findings of serous detachments and pigmentary macular changes are remarkable, while at the same time these patients have surprisingly very few symptoms. This is in contrast to patients who develop melanoma associated retinopathy (MAR) who are very symptomatic early in the disease, but with more subtle retinal findings. CONCLUSION: Monoclonal antibody treatment is changing the survival rates in metastatic disease making early diagnosis even more important. Exudative polymorphous vitelliform maculopathy (EPVM) needs to be recognized early to avoid delay in diagnosis of metastatic disease.

Cancer-induced, immune-mediated ocular degenerations.

The means whereby vision can be lost from a disease located distant from the eye include autoimmunity, with sensitization resulting from extraocular stimuli, a process illustrated here by the immunologic confusion caused by cancers. The uncontrolled proliferation of malignancies commonly involves the expression of components of the central nervous system, but a damaging loss of tolerance is rare. When autoimmunity does develop, organ-specific antigens are more often involved than the more generalized and widely disseminated common neuronal components. A focus upon a single antigen is typical of the immune-mediated paraneoplasia, a collection of syndromes identified by unusual antibody reactions. This review provides an outline of the immunologic trail that led to the recognition of autoimmunity in paraneoplastic ocular degenerations, how specific antibody reactions aid in diagnosis, and the possibility of including antibodies in modes for sight-saving intervention. 'Those who do not know history are destined to repeat it'.

Autoimmune retinopathy with RPE hypersensitivity and 'negative ERG' in X-linked hyper-IgM syndrome.

PURPOSE: To report the clinical, electrophysiological, and immunological features of a patient with X-linked hyper-IgM immunodeficiency syndrome type 1 (HIGM1) accompanied by a novel type of autoimmune retinopathy, including retinal pigment epithelium (RPE) hypersensitivity. METHODS: Comprehensive ophthalmological examinations, electrophysiological function testing, and inquiries into the immunological status of a 13-year-old presenting with subacute loss of vision in association with a molecularly confirmed diagnosis of HIGM1 were performed. The patient was genotyped by a PCR-based sequence tag content mapping strategy to define the genetic defect within the causative X-HIM gene TNFSF5. Since conventional allogenic bone marrow transplantation has been reported to cure HIGM1, a peripheral blood stem-cell transplantation was performed. RESULTS: (1) The patient's reduced visual acuity included prolonged dark adaptation and visual field constriction. Electrophysiology revealed a 'negative ERG' indicating post-receptoral dysfunction. (2) Initial immunological examination of the patient's serum identified abnormal antibody activity with components of the photoreceptors and the inner nuclear layer. The patient later developed indications of RPE hypersensitivity. A massively reduced light-peak to dark-trough ratio of the EOG slow oscillations (L/D ratio) corresponded to impaired RPE-photoreceptor complex function. (3) Molecular genetic analyses revealed the patient to be nullizygous for the tumor necrosis factor ligand member 5 gene (TNFSF5; CD40LG). A large chromosomal deletion of approximately 27.6-32.3 kb in size was identified in Xq26. (4) The transplant with its associated immunomodulation appeared to worsen rather than improve the patient's condition. CONCLUSIONS: The fundus appearance and electrophysiological function testing revealed indications of atypical retinal degeneration. However, the clinical course and the serological findings were consistent with those of ocular autoimmunity involving both antiretinal activity and RPE hypersensitivity. In this case, peripheral stem-cell transfusion with its associated chemotherapy failed to benefit the patient's vision; indications of autoimmunity appeared to increase following this treatment.

Paraneoplastic retinopathy associated with systemic follicular cell lymphoma.

The authors describe two rare cases of autoimmune retinopathy associated with follicular cell lymphoma, including a 54-year-old man who experienced nyctalopia for 1 year (patient 1) and a 59-year-old man who had bilateral loss of central vision for 6 months (patient 2). Visual field testing of patient 1 revealed nonspecific defects, and multifocal electroretinogram (ERG) testing showed mildly subnormal amplitudes more pronounced in the left than the right eye. Serologic testing detected antibodies against a 47-kD protein, presumed to be alpha-enolase. Goldmann perimetry of patient 2 showed dense central scotomas, and a full-field ERG revealed reduced amplitudes of bright scotopic responses. Serological testing yielded anti-bipolar cell antibodies. A variable presentation of autoimmune retinopathy can occur in the setting of follicular cell lymphoma. Disparate serum autoantibodies may have mediated the pathogenesis of retinal degeneration in these two patients and could explain the difference in course and severity of retinopathy.

Positive Auto-Antibody Activity With Retina and Optic Nerve in Smokers and Non-Smokers: The Controversy Continues.

Auto-antibodies assist with the diagnosis of ocular paraneoplastic syndromes and autoimmune ocular conditions; however, the frequency of positive test results as a possible precursor to future disease is unknown. The frequency of positive antibodies in heavy smokers who may be at risk for autoimmune-related retinopathy and optic neuropathy was evaluated. Serum antibody activity was evaluated through the use of Western blot reactions from pig retina and optic nerve extract. Fifty-one patients were included: 35 patients were smokers (average: 40.9 pack-year history) and 26 patients had no past smoking history. None of the patients had any visual complaints or known eye disease. Of the patients studied, 76.5% (39 patients: 18 smokers, 21 non-smokers) had positive antiretinal antibodies, and 19.6% (10 patients: 3 smokers, 7 non-smokers) had positive antioptic nerve antibodies. Anti-retinal antibodies were seen in a majority of randomly selected patients with and without a past smoking history. Anti-optic nerve bodies were less common, but more prevalent in those who never smoked. The specificity of these antibodies remains greatly uncertain and clinical correlation is warranted.

Outer retinal structure in patients with acute zonal occult outer retinopathy.

PURPOSE: To correlate visual function with high-resolution images of retinal structure using adaptive optics scanning laser ophthalmoscopy (AOSLO) in 4 patients with acute zonal occult outer retinopathy (AZOOR). DESIGN: Observational case series. METHODS: Four women, aged 18 to 51, with acute focal loss of visual field or visual acuity, photopsia, and minimal funduscopic changes were studied with best-corrected visual acuity (BCVA), Goldmann kinetic and automated perimetry and fundus-guided microperimetry, full-field and multifocal electroretinography (ffERG and mfERG), spectral-domain optical coherence tomography (SD-OCT), and AOSLO imaging. Cone spacing was measured in 4 eyes and compared with 27 age-similar normal eyes. Additional functional testing in 1 patient suggested that cones were absent but rods remained. Serum from all patients was analyzed for anti-retinal antibody activity. RESULTS: In all patients vision loss was initially progressive, then stable. Symptoms were unilateral in 2 and bilateral but asymmetric in 2 patients. In each patient, loss of retinal function correlated with structural changes in the outer retina. AOSLO showed focal cone loss in most patients, although in 1 patient with central vision loss such change was absent. In another patient, structural and functional analyses suggested that cones had degenerated but rods remained. Anti-retinal antibody activity against a ∼45 kd antigen was detected in 1 of the patients; the other 3 patients showed no evidence of abnormal anti-retinal antibodies. CONCLUSIONS: Focal abnormalities of retinal structure correlated with vision loss in patients with AZOOR. High-resolution imaging can localize and demonstrate the extent of outer retinal abnormality in AZOOR patients.

Cancer-associated retinopathy with retinal periphlebitis in a patient with ovarian cancer.

PURPOSE: To describe a case of cancer-associated retinopathy (CAR) due to ovarian cancer presenting with retinal periphlebitis and a negative-type pattern electroretinogram (ERG). DESIGN: Case report. METHODS: Retrospective chart review. RESULTS: A negative-type ERG in the setting of progressive vision loss and retinal periphlebitis led to the discovery of metastatic ovarian cancer and ultimately the diagnosis of CAR. CONCLUSIONS: CAR can present with periphlebitis and a negative-type ERG. Greater awareness of these associations may allow for earlier detection of future cases.

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 therapy (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.

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.

Optic neuritis after anthrax vaccination.

OBJECTIVE: To report the occurrence of optic neuritis after anthrax vaccination in two patients. DESIGN: Observational case reports, review of literature. METHODS: Description of clinical history, examination, neuroimaging, and further studies in two patients experiencing optic neuritis in temporal association with anthrax vaccination. MAIN OUTCOME MEASURES: Visual acuity, visual fields. RESULTS: Two patients, 39 and 23 years of age, were seen with acute optic neuritis 1 month and 2 weeks, respectively, after anthrax booster vaccination and successfully treated with intravenous methylprednisolone. The first patient had a typical presentation and course of unilateral retrobulbar optic neuritis with excellent visual recovery. The second patient had a bilateral anterior optic neuritis and has required chronic immunosuppression to maintain his vision. Retinal and optic nerve autoantibodies were present in the second patient. No cross-reactive epitopes between anthrax vaccine and retina/optic nerve were identified. CONCLUSION: Optic neuritis is a potential adverse reaction of anthrax vaccination.

Progressive subretinal fibrosis and blindness associated with multifocal granulomatous chorioretinitis: A variant of sympathetic ophthalmia.

OBJECTIVE: To report a case of bilateral progressive subretinal fibrosis and blindness with multifocal granulomatous chorioretinitis occurring after intraocular surgery. We propose that this is a variant of sympathetic ophthalmia. DESIGN: Clinicopathologic case report. METHODS: The left enucleated globe was examined by histopathologic methods. The patient's sera were subjected to immunohistochemical studies against retinal antigens, and collagen 2 types in areas of fibrosis were identified. Polymerase chain reaction was used to test for herpes virus DNA in microdissected, formalin-fixed, paraffin-embedded tissue. RESULTS: The enucleated globe demonstrated histopathologic features similar to an entity previously described as progressive subretinal fibrosis with multifocal granulomatous chorioretinitis. The patient's sera demonstrated antibodies directed against retinal photoreceptors and pigment epithelium. Polymerase chain reaction for herpes virus was negative. Immunohistochemical studies demonstrated types III, IV, V, and VI collagen in areas of fibrosis. CONCLUSIONS: The clinical history along with the histopathologic and immunohistochemical findings suggest that progressive subretinal fibrosis with multifocal granulomatous chorioretinitis may represent a variant of sympathetic ophthalmia and that retinal autoimmunity may play a role in its pathogenesis.