Overview
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, 2] 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. [3] The onset of visual symptoms and detection of antibodies may precede the diagnosis of malignancy by months to years, the longest reported interval being 11 years. [4] 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), [5, 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. [10] 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, occasionally 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 techniques 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 young as 3 years have been described, [13] with no sex 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. [14] Occasional cases have been associated with non–small-cell lung cancer, Hodgkin lymphoma, and pancreatic, [15] prostate, [16] bladder, laryngeal, and colon cancers. [1, 17] MAR appears to be increasing in frequency relative to CAR, perhaps because of a decrease in 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 years) and a slight male preponderance. [10]
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 experience photosensitivity, prolonged glare after light exposure (hemeralopia), reduced visual acuity and central vision, 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 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. [10] 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. [10] However, most patients with MAR experience 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 changes occur over time, including attenuation of retinal arterioles with thinning and mottling of the retinal pigment epithelium (RPE) and occasional optic disc pallor. In rare 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 43 patients with MAR were as follows: 19 (44%) patients had normal fundus findings at presentation, 13 (30%) had vascular attenuation, and 12 (28%) had RPE changes. Vitreous cells were present in 13 (30%) patients, and 10 (23%) had optic disc pallor. [10]
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 inner retinal layers has been demonstrated with optical coherence tomography (OCT) in CAR [18] and in AR [19] .
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 reduced a and b waves in both photopic and scotopic conditions. Findings in MAR include a markedly reduced 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 important to maintain a high index of suspicion for a PR or AR in patients who present with newly onset progressive vision loss in the setting of a normal-appearing fundus on examination. The initial workup should include 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 and because kinetic perimetry may be more sensitive than static for detecting changes 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 techniques. 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 appropriate. Additional imaging studies to consider include CT of the abdomen and pelvis, mammography (in women), and total-body positron-emission tomography (PET) or CT/PET. Complete 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 sufficiently 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, additional 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 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 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) occasionally 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. Although 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 flat early in the course of disease.
It is important 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. [20]
Pathologic Findings
The first and most commonly identified antibody in patients with CAR is directed toward recoverin, a 23-kd retinal protein that is also expressed by some tumor cells. 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, including enolase, transducin, carbonic anhydrase II, arrestin, and others. Retinal antibodies directed toward retinal proteins approximating 40 kd have been identified in a patient with cancer-associated cone dysfunction. [21] Newly discovered autoantibodies directed against four unique 23-kd proteins have been also identified: guanylyl cyclase-activating proteins (GCAP1 and GCPA2), heat shock protein 27 (HSP27), and Rab6A GTPase (Rab6A). It is suspected that these autoantigens may be involved in the pathogenicity of CAR and AR. [22] Efforts at standardization of laboratory testing and correlation between specific antiretinal antibodies and malignancies are ongoing. [23]
Antibodies to the photoreceptor cell-specific nuclear receptor (PNR) gene product have also been identified in some patients with CAR. [24] These antibodies initiate a cascade of events, leading to increased phosphorylation of rhodopsin, which, in turn, increases intracellular levels of calcium and activates apoptotic pathways, causing photoreceptor cell death. [25, 26]
Patients with MAR have IgG autoantibodies directed against rod bipolar cells, a 22-kd neuronal antigen [27] and transducin [28] . These same antibodies were identified in a patient with colon cancer; therefore, this finding is not specific. Antibodies directed against the 35-kd retinal Müller-cell layer have been found in some patients with AR (eg, 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 transsynaptic ganglion-cell atrophy.
Therapy
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 may result in modest visual recovery in some cases, but more often the most that can be accomplished is disease stabilization. [29] 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. [30, 31, 32]
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. [33] 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. Other research efforts involve activation of recoverin-specific antitumor cytotoxic T lymphocytes. Rituximab was found to be beneficial in a patient with CAR [34] and autologous hematopoietic stem cell transplantation in a case of AR and optic neuropathy. [35]
A study of 30 patients with PR or AR found improvement in 21 (70%) using immunosuppressive agents. [36] In this report, the best response occurred in those with cancer-associated disease (improvement in 6 of 6 cases). Various agents were used, including corticosteroids (periocular and systemic), azathioprine, intravenous immunoglobulin, mycophenolate mofetil, cyclosporine, infliximab, and various combinations of these immunomodulatory medications.
Illustrative Cases
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 in the right eye and 20/25 in the left eye. The visual field in the right eye showed a ring scotoma and was normal in the left eye. Dilated funduscopic 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.
Goldmann perimetry in the above patient with bilateral sequential visual loss and photopsias. In the right eye, there is a dense ring scotoma breaking out to the periphery. In the left eye, there is an inferior arcuate scotoma that breaks out nasally.
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.
Goldmann perimetry in the above patient shows several scotomas between 10 and 20 degrees in each eye, almost coalescing to form a ring scotoma. While a normal foveal peak is noted, there is marked generalized decrease in the perifoveal responses in each eye.
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 kd (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.
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Multifocal electroretinogram.
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Multifocal electroretinogram.
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Goldmann perimetry in the above patient shows several scotomas between 10 and 20 degrees in each eye, almost coalescing to form a ring scotoma. While a normal foveal peak is noted, there is marked generalized decrease in the perifoveal responses in each eye.
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Goldmann perimetry in the above patient with bilateral sequential visual loss and photopsias. In the right eye, there is a dense ring scotoma breaking out to the periphery. In the left eye, there is an inferior arcuate scotoma that breaks out nasally.
