Cancer Associated and Related Autoimmune Retinopathies

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Paraneoplastic and autoimmune retinopathies belong to a spectrum of uncommon ophthalmic disorders in which autoantibodies directed at various retinal proteins cause progressive vision loss. [1, Two] Paraneoplastic retinopathies (PR) are characterized by retinal antibodies in the setting of an underlying malignancy, whereas autoimmune retinopathies (AR) are characterized by autoantibodies directed against retinal proteins without a known malignancy. [Three] The onset of visual symptoms and detection of antibodies may precede the diagnosis of malignancy by months to years, the longest reported interval being eleven years. [Four] In some cases, patients with an underlying malignancy have been found to have high titers of antiretinal antibodies but no evidence of visual loss.

Specific paraneoplastic and autoimmune retinopathies that have been identified include cancer-associated retinopathy (CAR), [Five, 6] melanoma-associated retinopathy (MAR), [7] antienolase retinopathy, [8] anticarbonic anhydrase II retinopathy, [9] and cancer-associated cone dysfunction. [9] In most cases of CAR, vision loss occurs before a malignancy has been diagnosed. In contrast, MAR often occurs after a previously diagnosed cutaneous melanoma, and the vision loss is often accompanied by a recurrence or metastasis. [Ten] Paraneoplastic syndromes involving the optic nerves are less common than those involving the retina. The best-defined of these syndromes is associated with collapsin response-mediator protein-5 (CRMP-5)–immunoglobulin G (IgG) and manifests as bilateral optic neuropathy with retinitis and vitritis. [11]

The clinical features of paraneoplastic retinopathy and autoimmune retinopathy are similar. Patients typically present with rapid, painless vision loss associated with flashing lights (photopsias) and photosensitivity. [12] Symptoms are usually bilateral, periodically sequential, and progressive over weeks to months. In patients with antienolase retinal antibodies, symptoms are often less acute and progression is slower. [8]

Findings on retinal examination are usually 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 technologies to identify circulating retinal antibodies.

Epidemiology

In general, PR and AR are uncommon disorders; their exact prevalence, however, is unknown. They usually affect older adults, but patients as youthful as three years have been described, [13] with no hookup predilection. CAR is thought to be the most common form of PR. The malignancy most commonly associated with this disorder is small-cell lung cancer, followed by gynecologic (uterine and cervical) and breast cancers. Occasional cases have been associated with non–small-cell lung cancer, Hodgkin lymphoma, and pancreatic, guts, bladder, laryngeal, and colon cancers. [1] MAR emerges to be enhancing in frequency relative to CAR, perhaps because of a decrease in cases of lung cancer. A summary of the available information on sixty two patients with MAR exposed an average age of fifty seven years (range, 30-78 years) and a slight masculine preponderance. [Ten]

Clinical Findings

Symptoms and signs depend on which retinal elements are affected. CAR affects both rods and cones, whereas MAR is typically characterized by antibodies directed toward bipolar cells that interfere with rod function. Patients with cone-associated retinopathy have dysfunction limited to only cones.

Individuals with cone dysfunction practice photosensitivity, prolonged glare after light exposure (hemeralopia), diminished visual acuity and central vision, and loss of color vision. Individuals with rod dysfunction have difficulty watching in dim illumination (nyctalopia), prolonged dark adaptation, and peripheral field loss. In either case, positive visual phenomena are prominent, including flashing lights (photopsia), 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.

On examination, 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 early in their course. [Ten] For example, in the series by Keltner et al, visual acuity was 20/60 or better in 82% at presentation but in only 30% at last follow-up. [Ten] However, most patients with MAR practice progressive visual loss, especially in the peripheral visual field.

Funduscopic findings at presentation are often normal in all forms of PR and AR. However, characteristic switches occur over time, including attenuation of retinal arterioles with thinning and mottling of the retinal pigment epithelium (RPE) and occasional optic disc pallor. In infrequent cases of CAR or MAR, vitreous cells, arteriolar sheathing, and periphlebitis may be present, particularly late in the course of disease. As reported by Keltner et al, funduscopic findings in forty three patients with MAR were as goes after: nineteen (44%) patients had normal fundus findings at presentation, thirteen (30%) had vascular attenuation, and twelve (28%) had RPE switches. Vitreous cells were present in thirteen (30%) patients, and ten (23%) had optic disc pallor. [Ten]

Fluorescein angiography is often performed to exclude other entities as potential causes of vision loss. Findings are usually normal, but in occasional cases, there is mild peripheral vascular leakage consistent with vasculitis. Thinning of the internal retinal layers has been demonstrated with optical coherence tomography (OCT) in CAR [14] and in AR [15] .

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 with diminished a and b flaps in both photopic and scotopic conditions. Findings in MAR include a markedly diminished or absent dark-adapted b wave (electronegative waveform), which indicates bipolar and Müller cell dysfunction with preserved photoreceptor function. [7] Multifocal ERG (MERG) is useful for evaluating select cases in which visual-field loss is localized, for monitoring disease progression, and for correlating with visual-field loss.

Workup

It is significant to maintain a high index of suspicion for a PR or AR in patients who present with freshly onset progressive vision loss in the setting of a normal-appearing fundus on examination. The initial workup should include a total 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 and because kinetic perimetry may be more sensitive than static for detecting switches in this disorder. 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 elements involved. In select cases, MERG may be helpful.

A definitive diagnosis of PR or AR requires the demonstration of antiretinal antibodies. Tests for these antibodies are now available commercially (eg, from Athena Diagnostics and the Ocular Immunology Laboratory at Oregon Health Sciences University) and at several research laboratories, including the University of California at Davis, Ophthalmology Research Laboratories. However, results of such laboratory testing are not always definitive. On occasion, individuals without clinical evidence of retinopathy have these antibodies, and, in some cases of presumed PR or AR, the antibodies cannot be identified with current technologies. In one report, it is estimated that up to 35% of retinal antibodies are not detected in patients with presumed CAR. [1]

In any patient with suspected CAR and without a known malignancy, a chest radiograph should be obtained. If the result is normal and the index of suspicion of CAR remains high, a chest CT scanning is adequate. Extra imaging studies to consider include CT of the abdomen and pelvis, mammography (in women), and total-body positron-emission tomography (PET) or CT/PET. Finish physical examination, including pelvic and breast examinations for women, is also recommended.

Differential Diagnoses

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 reasonably distinct to distinguish optic nerve disease from retinal disease and therefore obviate extensive neurologic testing.

Symptoms of hemeralopia or nyctalopia (degradation of vision in bright or dim lighting, respectively), positive visual phenomena, prolonged photostress times (as determined from the history or examination), and ring scotomas indicate retinal disease, even in the absence of funduscopic abnormalities, and should prompt electrophysiologic studies. If the ERG findings clearly confirm a retinal disorder, extra neurodiagnostic testing is unnecessary.

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 tobacco and alcohol use, dietary habits, exposure to environmental toxins, 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 sophisticated. 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 malignant 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, hydroxychloroquine, and thioridazine.

The clinical findings of acute zonal occult outer retinopathy (AZOOR) from time to time overlap with PR/AR, sometimes causing diagnostic confusion. In AZOOR, the nonseeing areas are more sharply demarcated from the surrounding areas, the involvement is usually unilateral, and the disease has a predilection for the peripapillary area. Albeit MERG demonstrates the abnormality well, findings from full-field ERG are generally normal, in distinction from PR in which ERG findings are markedly attenuated or vapid early in the course of disease.

It is significant to ask patients with a history of melanoma and other systemic cancers if they have ever received chemotherapeutic treatment. It has recently been discovered that mitogen-activated protein kinase (MEK) inhibitors (eg, binimetinib) have been associated with a dose-dependent, transient serous neurosensory detachment with eventual retinal atrophy and preserved retinal function. Retinal findings related to these medication side effects should not be confused with those of a PR. [16]

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