Cancer Associated and Related Autoimmune Retinopathies 

Cancer- and autoimmunity-associated retinopathies belong to a spectrum of uncommon ophthalmic disorders in which autoantibodies directed at various retinal components cause progressive vision loss. In most cases, an evaluation reveals an underlying malignancy, placing this condition in the category of paraneoplastic syndromes. In rare cases, no such malignancy is found, and patients are considered to have autoimmune retinopathy (AR), which is also termed recoverin-associated retinopathy (RAR). In some cases, patients with an underlying malignancy have been found to have high titers of antiretinal antibodies but no evidence of visual loss.

The clinical features of paraneoplastic retinopathy (PR) and AR are generally similar. Specific forms of PR that have been identified include cancer-associated retinopathy (CAR), melanoma-associated retinopathy (MAR), and cancer-associated cone dysfunction. Paraneoplastic syndromes involving the optic nerves are less common than those involving the retina. The best defined of these paraneoplastic syndromes is associated with collapsin response-mediator protein-5 (CRMP-5)-immunoglobulin G (IgG) and manifests as bilateral optic neuritis with retinitis and vitritis.

Patients with PR and AR typically present with rapid, painless vision loss associated with photopsias and photosensitivity. Symptoms are usually bilateral, occasionally sequential, and progressive over weeks to months.

Findings on retinal examination may be normal early in the course of the disease, posing a diagnostic challenge in some cases. Markedly abnormal electroretinographic (ERG) findings indicate the correct diagnosis, which can usually be confirmed with immunofluorescence techniques to identify circulating retinal antibodies.

In most cases of CAR, vision loss occurs before malignancy is diagnosed. In contrast, vision loss due to MAR usually occurs in patients whose melanoma is already diagnosed, often at the stage of metastatic spread. In an excellent review, Keltner et al summarize the clinical and immunologic findings in 11 new patients with MAR and 51 reported in the literature.^[1] Chan reviewed all PRs and optic neuropathies.^[2]

In general, PR and AR are uncommon disorders; their exact prevalence is unknown. They usually affect older adults, with no sex predilection. CAR is thought to be the most common form of PR. The malignancy most commonly associated with these disorders is small-cell lung cancer, followed by gynecologic and breast cancers. Occasional cases have been associated with non–small-cell lung cancer, Hodgkin lymphoma, and pancreatic, prostate, bladder, laryngeal, and colon cancers.

MAR appears to be increasing in frequency relative to CAR, perhaps because of a decrease in the cases of lung cancer. A summary of the available information on 62 patients with MAR revealed an average age of 57 years (range, 30-78 y) and a slight male preponderance.

To some extent, symptoms and signs depend on which retinal elements are affected. CAR affects both rods and cones. In MAR, antibodies directed toward bipolar cells interfere with rod function. Patients with cone-associated retinopathy have dysfunction limited to only cones.

Individuals with cone dysfunction experience photosensitivity, prolonged glare after light exposure (hemeralopia), reduced visual acuity, and loss of color vision. Individuals with rod dysfunction have difficulty seeing in dim illumination (nyctalopia), prolonged dark adaptation, and peripheral field loss. In either case, positive visual phenomena are often prominent, including flashing lights, flickering, smoky or swirling vision, and other entoptic symptoms. Some patients report transient dimming of vision, which may be mistaken for retinovascular disease.

Occasional cases with overlap features occur, including the patient with typical findings of MAR but in whom examination findings are variable. Patients with CAR usually have prominent involvement of central vision, resulting in markedly decreased visual acuity, loss of color vision, and central scotomas. In some cases, visual field testing shows paracentral scotomas that progress to classic ring scotomas. Photostress recovery times are typically prolonged. In contrast, patients with MAR often have near-normal visual acuity, color vision, and central visual fields, at least at presentation. Peripheral or midperipheral field loss can usually be demonstrated.

In Keltner's review of 34 patients with MAR, 28 (82%) had initial visual acuity of 20/60 or better.^[1] Visual field testing showed generalized constriction in 18 (67%) of 27 patients; 18 (67%) of 27 patients also had central or paracentral scotomas. However, progression typically occurs. In this series, the patients' last recorded visual acuity was significantly decreased, with only 10 patients having visual acuity of better than 20/60.

Funduscopic findings at presentation are often normal. However, characteristic changes occur over time and include attenuation of the arterioles, with thinning and mottling of the retinal pigment epithelium (RPE). In occasional cases of CAR or MAR, vitreous cells, arteriolar sheathing, and periphlebitis may be present, particularly late in the course of disease. As Keltner reported, fundus findings in 43 patients with proven MAR were as follows: 19 (44%) patients had normal fundus findings at presentation, 13 (30%) had vascular attenuation, and 12 (28%) had RPE changes.^[1] Vitreous cells were present in 13 (30%) patients, and 10 (23%) had optic-disc pallor.

Fluorescein angiography is often performed to exclude other entities as potential causes of vision loss. Findings are usually normal, but, in occasional cases, fluorescein angiography may demonstrate mild peripheral vascular leakage consistent with vasculitis.

Thinning of the inner retinal layers in CAR has been demonstrated with optical coherence tomography (OCT).

The findings from full-field (Ganzfeld) ERG are almost always abnormal; specific findings depend on the predominance of cone versus rod dysfunction. Patients with CAR usually have absent cone responses. Findings in MAR include a markedly reduced or absent dark-adapted b wave, which indicates bipolar and Müller cell dysfunction.

Multifocal ERG (MERG) may be useful in select cases in which visual field loss is localized. In addition, some authors have used MERG to quantify the loss of electrical activity and to correlate this finding with results of Goldmann perimetry.

Maintaining a high index of suspicion based on the clinical findings is helpful. The initial workup includes a full assessment of the patient's visual function, including color vision and visual field testing. Goldmann perimetry is preferred because it readily tests the peripheral field; if automated perimetry is performed, the test should be adapted to include the peripheral field. Full-field ERG is crucial for localizing the disease process to the retina and for further defining the retinal layers involved. In select cases, mfERG may be helpful.

A definitive diagnosis of CAR or MAR requires the demonstration of antiretinal antibodies. Tests for these antibodies are now available commercially (eg, from Athena Diagnostics) and at several research laboratories, including the University of California at Davis, Ophthalmology Research Laboratories. Results of such laboratory testing are not always definitive. In many cases, individuals without clinical evidence of retinopathy have these antibodies, and, in some cases of presumed CAR, the antibodies cannot be identified with current techniques.

In any patient with suspected CAR and without a known malignancy, a chest radiograph should be obtained. If the result is normal, a CT scan of the chest is appropriate. Additional imaging studies for a possible primary neoplasm include CT of the abdomen and pelvis, mammography (for women), and total-body positron emission tomography (PET). Complete physical examination, including pelvic and breast examinations for women, is also recommended.

Acute or subacute unilateral or bilateral vision loss with a normal-appearing fundus suggests the possibility of retrobulbar optic neuropathy. Specific entities to consider include compressive orbital and intracranial lesions, demyelinating disease, ischemia, toxicity, and hereditary disorders. In the ideal case, the clinical findings are sufficiently distinctive to distinguish optic nerve disease from retinal disease and therefore obviate extensive neurologic testing.

Symptoms of hemeralopia or nyctalopia, positive visual phenomena, prolonged photostress times (as determined from the history or examination findings), and ring scotomas all suggest the possibility of retinal disease, even in the absence of funduscopic abnormalities, and prompt electrophysiologic studies. If the ERG findings clearly confirm a retinal disorder, additional neurodiagnostic testing is not indicated.

Patients with cancer-associated cone dysfunction have bilateral central vision loss with poor color vision and central scotomas. These findings are also compatible with toxic-nutritional optic neuropathy or hereditary optic neuropathy. Patients with these findings should be questioned about possible tobacco and alcohol use, dietary habits, use of potentially toxic medications, and a family history of similar problems. MERG should be effective for distinguishing optic neuropathy from maculopathy in these patients.

In patients with unexplained vision loss and a history of malignancy, the differential diagnosis may be complex. Workup for metastatic disease as the cause of the vision loss should include contrast-enhanced MRI of the head and orbits and lumbar puncture for cytologic examination. Some chemotherapeutic agents, such as vincristine and carmustine (BCNU), can cause optic neuropathy. Patients who have received cranial radiation are also at risk for vision loss, which is usually identifiable on MRI. Vision loss in patients with metastatic disease may be due to infiltration of cancerous cells around the optic nerve. Diffuse melanocytic proliferation is a possibility in cancers originating from the reproductive tract, retroperitoneal zone, or lungs. For reasons that are poorly understood, patients with this proliferation develop an orange pigment deposit at the level of the RPE; fluorescein angiography shows hyperfluorescence.

Once it is clear that the patient's vision loss is due to photoreceptor dysfunction, the differential diagnosis is narrowed to paraneoplastic syndromes, hereditary photoreceptor degeneration (eg, cone dystrophy, retinitis pigmentosa), and toxic retinopathy. The time course in patients with hereditary retinopathies is generally longer than that of patients with acquired disease; progression occurs over years rather than weeks to months. Patients should be questioned regarding the use of potential retinal toxins, such as chloroquine, Plaquenil, and Mellaril. A family history of late-onset visual dysfunction is helpful, when present.

Cases of acute zonal occult outer retinopathy (AZOOR) are occasionally confused with PR. In AZOOR, the nonseeing areas are sharply demarcated from the surrounding areas, the involvement is usually unilateral, and the disease has a predilection for the peripapillary area. Although mfERG demonstrates the abnormality well, findings from full-field ERG are generally normal, in distinction from PR in which ERG findings are markedly attenuated or flat early in the course of disease.

The first and most commonly identified antibody in patients with CAR is directed toward recoverin, a 23-kDa retinal protein that some tumor cells also express. Since the original identification of recoverin and its role in the pathophysiology of CAR, antibodies that react with a number of other retinal antigens have been identified.

Antibodies to the photoreceptor cell-specific nuclear receptor (PNR) gene product have also been identified in some patients with CAR. These antibodies initiate a cascade of events, leading to increased phosphorylation of rhodopsin, which, in turn, increases intracellular levels of calcium, which activates apoptotic pathways, resulting in photoreceptor cell death.

Patients with MAR have IgG autoantibodies that react with human rod bipolar cells. These same antibodies were identified in a patient with colon cancer rather than melanoma; therefore, this finding is not specific. Antibodies directed against the 35-kDa retinal Müller-cell layer have been found in some patients with AR (ie, those without evidence of underlying malignancy).

Postmortem examination of eyes with CAR demonstrates diffuse photoreceptor degeneration with or without inflammation. Ganglion cells and retinal vasculature are spared. In MAR, bipolar neurons in the inner nuclear layer are markedly decreased, with evidence of transynaptic ganglion-cell atrophy.

The overall prognosis of patients with PR is not good. Surgery, chemotherapy, and radiation therapy to treat the primary tumor do not appear to alter the visual prognosis. Various immunotherapies result in modest visual recovery in some cases. Corticosteroids have been shown to decrease antibody titers in patients with CAR and may stabilize their vision, but they do not usually reverse vision loss. Anecdotal reports describe improvement in both CAR and MAR with high-dose intravenous methylprednisolone, plasmapheresis combined with steroids, or intravenous immunoglobulin (IVIG); however, the treatment results are largely disappointing.

Espandar et al described a beneficial response in a patient with CAR treated with alemtuzumab, a monoclonal antibody that is used for the treatment of various B-cell mediated disorders.^[3] Calcium antagonists aimed at blocking antibody-mediated apoptosis were found to be protective against antirecoverin antibodies in an animal model, but the efficacy in humans has not yet been demonstrated. In addition, azathioprine and gabapentin were reported to be of benefit in a patient with MAR.

Other research efforts involve activation of recoverin-specific antitumor cytotoxic T lymphocytes.

Case 1

A 60-year-old plumber developed painless visual loss in the right eye accompanied by intermittent "swirling clouds of smoke", occasional dim flashes of light, and photophobia. Visual acuity was count fingers OD and 20/25 OS. The visual field in the right eye showed a ring scotoma and was normal in the left eye. Dilated fundus examination and fluorescein angiography were normal. A retrobulbar optic neuropathy was suspected, but an MRI of the brain and orbits with gadolinium was normal. He received a tentative diagnosis of posterior ischemic optic neuropathy. Two months later, similar though milder visual loss developed in the left eye (see the image below). As before, the fundus appearance was normal.

A full-field ERG was nearly unrecordable under both scotopic and photopic conditions, indicating severe dysfunction of both rods and cones. Serologic testing showed antibodies to recoverin, diagnostic of cancer-associated retinopathy (CAR). A chest radiograph was normal, but CT of the chest revealed a small lesion, which, on biopsy, proved to be a small-cell lung carcinoma. His primary tumor was treated with radiation and chemotherapy, and he received a course of high-dose intravenous corticosteroids followed by rituximab. Vision stabilized but unfortunately showed minimal improvement.

Case 2

A 65-year-old dental hygienist presented with a 3-year history of flashing, squiggly lines around the periphery of her vision in both eyes, initially intermittent but more persistent over time. Visual acuity, color vision, and pupillary responses were normal. Goldmann perimetry (shown in the image below) showed several scotomas between 10 and 20 degrees in each eye, almost coalescing to form a ring scotoma. Fundus appearance and fluorescein angiography were normal.

Multifocal ERG (images below) showed decreased amplitude surrounding fixation, corresponding to the location of the scotomas. Her serum was negative for anti-recoverin antibodies but positive for antibodies to 30 kDa (carbonic anhydrase II). In addition, immunohistochemistry showed staining of some cells in the bipolar cell layer. She received a diagnosis of autoimmune retinopathy and has been followed conservatively.