Charles E. Thirkill

Cancer-Associated Retinopathy (CAR Syndrome) with Antibodies Reacting with Retinal, Optic-Nerve, and Cancer Cells

A VARIETY of neurologic disorders are associated with different forms of cancer.1 2 3 4 5 6 7 Secondary neurologic effects that become manifest in the absence of metastasis are collectively called ...

Clinical and immunologic characteristics of melanoma-associated retinopathy syndrome: eleven new cases and a review of 51 previously published cases.

Objective To evaluate the signs, symptoms, and immune responses of patients with melanoma-associated retinopathy (MAR) syndrome. Materials and Methods We reviewed the clinical and immunologic findings of 62 MAR syndrome patients. They include 25 patients from our institution (11 not previously reported) and 37 patients reported from other institutions. Results There were 33 men and seven women (no gender information is available for the remaining 22 cases). Age at onset of the visual disturbance averaged 57.5 years (range, 30–78). Visual acuity of 20/60 or better was initially present in 82%. Fundus examination was normal in 44%, optic disc pallor was present in 23%, and retinal vessel attenuation was present in 30%. Vitreous cells were present in 30%. The latency from melanoma diagnosis to recognition of MAR syndrome averaged 3.6 years (range, 2 months to 19 years). Seven patients sustained visual improvement with various treatment regimens, especially with intravenous immunoglobulin and cytoreductive surgery (metastasectomy). Indirect immunohistochemical staining of the bipolar layer was typical, but several other retinal elements were also reactive. Tissue from a metastatic melanoma excised from one of the patients expressed antigens that reacted with antiretinal antibodies. Conclusion MAR syndrome demonstrates diverse clinical and immunologic features. Treatment, especially intravenous immunoglobulin and cytoreductive surgery (metastasectomy), improves vision in some cases.

Paraneoplastic retinopathy: a novel autoantibody reaction associated with small-cell lung carcinoma.

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 accompained 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.

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.

Melanoma-associated retinopathy: high frequency of subclinical findings in patients with melanoma.

Summary Background Melanoma‐associated retinopathy (MAR) is a paraneoplastic syndrome with symptoms of night blindness, light sensations, visual loss, defect in visual fields, and reduced b‐waves in the electroretinogram. Patients with MAR often suffer from a sudden onset of ocular symptoms that are believed to result from antibody production against melanoma‐associated antigens that cross‐react with corresponding epitopes on retinal depolarizing bipolar cells.

Lymphoma-associated retinopathy

OBJECTIVE To describe the clinical, electrophysiologic, and serologic findings in a patient with retinal degeneration associated with Hodgkins 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 Hodgkins 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 Hodgkins 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.

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.

Incidence of antiretinal antibodies in melanoma: screening of 77 serum samples from 51 patients with American Joint Committee on Cancer stage I-IV.

Background  Patients with melanoma‐associated retinopathy (MAR) experience different visual symptoms caused by the production of antitumoral antibodies that cross‐react with retinal epitopes. Immunofluorescence assays of serum from patients with MAR on sectioned monkey or human retina characteristically reveal antibody activity located within the inner nuclear layer, with a focus of activity upon the membranes of bipolar cells.

Antibody Indications of Secondary and Superimposed Retinal Hypersensitivity in Retinitis Pigmentosa

Antibody reactions with recognized retinopathy-inducing retinal antigens may be interpreted to reflect ongoing autoimmune events responsible for some forms of vision loss. We sought evidence of secondary and superimposed retinal hypersensitivity indicated by such antibody reactivity in a random group of patients with retinitis pigmentosa. We identified patterns of immunologic reactivity within members of a group of 52 patients with retinitis pigmentosa, which suggests some patients with retinitis pigmentosa may experience consequential superimposed retinal hypersensitivity. Identifying subgroups of patients with retinitis pigmentosa who exhibit indications of retinal hypersensitivity to known uveitopathogenic retinal proteins may permit the reduction of their rate of retinal degradation by immunomodulation.

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.’