Paraneoplastic retinopathy …

Neuro-Oncology

Updated 08.20.2024
Released 11.11.1994
Expires For CME 08.20.2027

Paraneoplastic retinopathy

Authors: Shira S Simon MD MBA, Timothy Janetos MD MBA, Nicholas J Volpe MD

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Editor: Rimas V Lukas MD

Paraneoplastic retinopathy

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Introduction

Overview

Paraneoplastic disorders are the remote effects of cancer not due to direct tumor invasion or metastasis and can affect any part of the nervous system. Neurologists, oncologists, and ophthalmologists need to be aware that this includes the retina. Retinal neuronal dysfunction and degeneration may occur in association with a number of systemic neoplasms, including, most notably, melanoma and small-cell lung carcinoma. In certain conditions, for many patients, vision loss is the presenting feature of the associated tumor, whereas others may present even years after the initial tumor diagnosis. Some affected patients have circulating antibodies against retinal antigens; these antibodies serve as diagnostic markers for the condition and may also play a role in pathogenesis. With the advent of immune checkpoint inhibitors and the prolonged lifespan of cancer patients, paraneoplastic retinopathy may be increasing in incidence. This article summarizes the clinical features, pathogenesis, and management strategies for the three primary paraneoplastic retinal disorders: cancer-associated retinopathy, melanoma-associated retinopathy, and paraneoplastic acute exudative polymorphous vitelliform maculopathy.

Key points

	• Paraneoplastic retinopathy is a rare entity associated with a variety of neoplasms, most commonly small-cell lung carcinoma or melanoma.
	• In most patients with cancer-associated paraneoplastic retinopathy, subacute vision loss is the presenting feature of the malignancy, whereas vision loss develops after the melanoma diagnosis in the majority of patients with melanoma-associated paraneoplastic retinopathy.
	• Diagnosis of paraneoplastic retinopathy is difficult. Diagnosis can be supported by multimodal ophthalmic imaging (most notability, ERG) and supported by the presence of retinal autoantibodies. However, there is no confirmatory test for paraneoplastic retinopathy.
	• Most patients with paraneoplastic retinopathy have one or more antiretinal autoantibodies.
	• There is no proven treatment for cancer-associated retinopathy or melanoma-associated retinopathy, and prognosis is often poor. However, treating the primary tumor in conjugation with immunosuppressive or immunomodulatory therapy may improve outcomes.
	• Paraneoplastic acute exudative polymorphous vitelliform maculopathy may be reversible with a fairly good visual prognosis but is often associated with advanced systemic disease.

Historical note and terminology

The first well-documented cases of “photoreceptor degeneration as a remote effect of cancer” were reported in 1976 by Sawyer and colleagues (123). The cases were of three female patients with bronchial carcinoma who presented with vision loss before cancer diagnosis, ERG findings of nearly depressed retinal function, and ring scotomas on visual field testing. These were likely the first described cases of cancer-associated retinopathy. In 1982, a sample of patients with small-cell carcinoma of the lung had the first measured antiretinal antibodies, which postulated a potential antibody-mediated process (75). However, the term “paraneoplastic autoimmune retinopathy” encompasses patients with heterogeneous tumor associations and clinical features and probably represents more than one pathophysiologic mechanism.

Clinical manifestations

Presentation and course

Cancer-associated retinopathy. In many patients with cancer-associated retinopathy, the visual symptoms are the presenting feature of the tumor, preceding discovery of the tumor by intervals ranging from several months to 2 or more years. Mean age of patients is 65 years. Both men and women demonstrate equal incidence (122). The signs and symptoms of paraneoplastic retinopathy nearly always involve both eyes, but asymmetry can often be present, especially early in the course of the disease process. Cancer-associated retinopathy causes a global dysfunction of both cones (day vision) and rods (night vision). Symptoms of cone dysfunction include glare or photosensitivity, so-called hemeralopia or day blindness, and reduced central vision and color vision. Most patients have visual field changes: visual field constriction, midperipheral loss, or central or paracentral scotomata (59; 97; 126). Some patients have central sparing of their visual fields (23; 27). In the case of primarily rod dysfunction, there may be dimming or blurring of vision; night blindness is common and may be the sole initial complaint. Because the disease causes dysfunction of retinal neurons, many patients report episodic obscurations or photopsias described as distortions, “sparkles,” “shimmering,” or bizarre images reflecting the dysfunction of damaged photoreceptors (67; 116). In most patients, the visual symptoms worsen over weeks to months, either in a steady or stepwise fashion. No well-documented cases of spontaneous improvement exist.

Visual acuity is usually severely impaired with decreased color vision. As a result of sometimes asymmetric retinal dysfunction, an afferent pupillary defect may be present. Funduscopic examination is typically normal, but attenuated arterioles, optic disc pallor, retinal pigment epithelial mottling, mild anterior uveitis or vitritis, and retinal vasculitis may be present. End-stage disease can be characterized by widespread chorioretinal atrophy and optic nerve atrophy that can resemble retinitis pigmentosa on fundoscopic examination (97).

Melanoma-associated retinopathy. The clinical features of patients in whom retinopathy is associated with melanoma differ somewhat from the clinical features of those with cancer-associated retinopathy (71; 69; 80). The majority of these patients develop visual symptoms after the diagnosis of melanoma (cutaneous or mucosal), with intervals of up to 10 years or more (111). The average latency period between the diagnosis of melanoma and melanoma-associated retinopathy is approximately 3.6 years (69). Visual symptoms can lead to the discovery of previously unsuspected systemic metastases (18; 09; 110). The predominant symptoms are bilateral night blindness and photopsia. Most patients additionally report floaters, shimmering, flickering, or pulsating photopsias early in the course of the disease. On initial presentation, vision may be better than in patients with cancer-associated retinopathy, with around 80% of patients presenting with 20/60 vision or better; most patients eventually develop decreased visual acuity and visual field abnormalities, including generalized constriction, central or paracentral scotomata, or arcuate defects (89; 143; 110; 69). As with cancer-associated retinopathy, fundoscopic examination is usually normal but may show findings of anterior uveitis, vitritis, or retinal vasculitis (66; 113). In later stages, widespread retinal atrophy, optic disc pallor, retinal vessel attenuation, and retinal pigmentary changes can be seen (69).

Paraneoplastic acute exudative polymorphous vitelliform maculopathy. Vitelliform retinopathy refers to multifocal serous detachments of the retina with accumulated subretinal material (61; 19; 12). Paraneoplastic acute exudative polymorphous vitelliform maculopathy is typically diagnosed after the primary tumor is known, and development may correlate with the burden of the systemic malignancy. In fact, most develop in the setting of metastatic disease. Patients may present with metamorphopsia, blurry vision, photopsias, and glare. Visual acuity is typically better preserved compared to cancer-associated retinopathy or melanoma-associated retinopathy. The fundoscopic examination is characterized by bilateral multifocal yellow-orange subretinal lesions.

Prognosis and complications

The clinical course of cancer-associated retinopathy or melanoma-associated retinopathy is usually one of deterioration over the course of weeks to months, in a gradual or stepwise fashion, to a level of severe visual impairment despite attempted treatment. No well-documented instances of significant spontaneous improvement are known. Paraneoplastic acute exudative polymorphous vitelliform maculopathy may have a reversible course with a good visual prognosis; however, diagnosis of paraneoplastic acute exudative polymorphous vitelliform maculopathy portends a rather dismal systemic disease state, with most patients dying within 4 years of diagnosis (122; 24).

Clinical vignette

A 64-year-old man with a past medical history notable for a 40-pack-per-year history of cigarette smoking developed painless blurring and dimming of the central field of vision in his left eye, with associated light sensitivity, especially when outside. Three weeks later, similar symptoms developed in his right eye, and the vision in both eyes progressively deteriorated. He also noted intermittent, colorful “sparkles” or halos around objects. Examination 6 weeks after the onset of symptoms demonstrated visual acuities of 20/400 in the right eye and 20/200 in the left eye with severe dyschromatopsia. Both pupils were minimally reactive to light, and there was no relative afferent pupillary defect. Ophthalmoscopy was normal except for attenuation of the retinal arterioles. Visual field testing revealed severe constriction bilaterally with a ring scotoma evident in the right eye. Electroretinogram demonstrated the near absence of the cone and rod response in both eyes. Brain MRI with and without contrast was within normal limits. Chest x-ray showed suspicious mediastinal widening, and chest CT scan showed hilar adenopathy. Bronchoscopy was diagnostic for small cell lung carcinoma. Staging workup showed no metastatic tumor. Serum was found to contain antirecoverin antibodies. The patient was placed on prednisone 60 mg/day (1 mg/kg) and chemotherapy with cisplatin and etoposide. After 1 month of prednisone and one cycle of chemotherapy, the patient's visual acuity and visual fields remained essentially stable. Steroids were tapered and discontinued, and complete tumor remission was attained after four cycles of chemotherapy. The patient’s vision remained stable but poor.

Biological basis

Etiology and pathogenesis

As with other neurologic paraneoplastic disorders, the leading theory of the pathogenesis of paraneoplastic retinopathy is that of molecular mimicry; an autoimmune response initially directed against tumor cell antigens subsequently “spills over” to attack photoreceptor cells and other retinal neurons (32). Tumors can develop similar antigens to those in remote areas of the body, such as the retina (73). The mechanism by which these antibodies cross the blood-retinal barrier is less clear (77). Most likely, there is a component of both an antibody and T-cell-mediated process that can more readily cross the blood-CNS barrier (01). Furthermore, production of vascular endothelial growth factor and placental growth factor by tumors may induce blood-retinal barrier breakdown (94). Ultimately, however, the pathogenesis of the condition is poorly understood.

Cancer-associated retinopathy. The most well-characterized autoantibody that is thought to play a role in cancer-associated retinopathy is recoverin. p53 tumor suppressor gene mutations within tumor cells are associated with increased expression of this protein, which is then targeted by the patient’s immune system. The recoverin gene is located near p53 (25). Recoverin is a calcium-binding protein located within the retinal photoreceptors and functions in the phototransduction cascade by modulating the phosphorylation of rhodopsin (17). Tissue collected from small-cell lung carcinoma has been shown to have high levels of recoverin peptides (84; 85; 16; 88). Anti-recoverin antibodies bind to photoreceptor cells, causing caspase-dependent apoptotic cell lysis. Intravitreal injection of anti-recoverin antibodies into rats produces abnormal electroretinograms and thinning of the inner and outer nuclear retinal layers (96; 85). Furthermore, rats or mice immunized with purified recoverin develop anti-recoverin antibodies, uveoretinitis with cellular infiltrates, and degeneration of photoreceptors (04; 83; 79). These same histopathologic changes can be reproduced by passive transfer of stimulated lymphocytes from rats immunized with recoverin into naive animals. Multiple other antibodies have been identified and proposed as potentially pathologic in cancer-associated retinopathy. Different antibodies may mediate different phenotypes of disease. For instance, cancer-associated cone dysfunction may be a subcategory of cancer-associated retinopathy in which only cones are affected related to the development of anti-enolase antibodies (111).

In terms of histology, features of cancer-associated retinopathy associated with small-cell lung carcinoma are severe; sometimes there is a total loss of the inner and outer segments of rods and cones and widespread degeneration of the outer nuclear layer (123; 23; 116; 04). Some eyes show patchy, mild infiltration of mononuclear cells around retinal arterioles. Varying changes in ganglion and bipolar cells as well as photoreceptor cells may be present (50). The retinal pigment epithelium and choroid are typically not affected. The ERG confirms global retinal dysfunction with severely decreased cone and rod function, even in the early stage of the disease (122).

Melanoma-associated retinopathy. In contrast to cancer-associated retinopathy, patients with melanoma-associated retinopathy have selective rod dysfunction with autoantibodies targeted against rod bipolar cells (142; 13). A few reported autopsies of patients with melanoma-associated retinopathy showed preservation of the photoreceptor cell layers but marked depletion of cell nuclei in the inner nuclear and bipolar layers (46). Several autoantibodies have been identified in patients with melanoma-associated retinopathy, the most specific being antibodies to transient receptor potential cation channel, subfamily M, member 1 (anti-TRPM1), which is expressed exclusively in retinal ON-bipolar cells (91). Three isoforms of TRPM1 have been identified in patients with melanoma-associated retinopathy (141). ERG can identify bipolar cell dysfunction in patients with melanoma-associated retinopathy.

Paraneoplastic acute exudative polymorphous vitelliform maculopathy. Likely, paraneoplastic acute exudative polymorphous vitelliform maculopathy is due to autoantibodies targeting the retinal pigment epithelium, leading to retinal pump dysfunction and the accumulation of subretinal material and fluid. Lipofuscin deposition creates yellow subretinal deposits. The antibody response to bestrophin-1 can produce a similar clinical picture to inherited bestrophinopathies (35; 29). PRDX3 antibodies, which target an RPE peroxidase protecting cells against oxidative damage, have also been identified (74). A single autopsied case of paraneoplastic vitelliform retinopathy showed multifocal retinal edema as well as atrophy, affecting mainly the inner nuclear layer, outer plexiform layer, and outer nuclear layers (12).

A note on antibodies. Most patients with paraneoplastic retinopathy have circulating antiretinal autoantibodies. As with other neurologic paraneoplastic disorders, the autoantibody specificities among patients with paraneoplastic retinopathy are heterogeneous (32; 48; 02; 118). The best-characterized antibodies include anti-recoverin in cancer-associated retinopathy, anti-TRPM1 in melanoma-associated retinopathy, and anti-bestropin-1 in paraneoplastic acute exudative polymorphous vitelliform maculopathy. However, many other autoantibodies have been proposed, and the utility of measuring antibodies for diagnosis and response to treatment has not been established.

Some patients with retinopathy associated with small-cell lung carcinoma or other carcinomas have no identifiable antiretinal antibodies, have autoantibodies that react with retinal target antigens distinct from recoverin (68), or have antibodies against recoverin plus antibodies against one or more other retinal antigens (55). Other identified retinal target antigens include a 65 kd heat shock protein (96; 97; 147), retinal enolase (03; 06; 51; 144), neurofilament triplet proteins (49; 132), the 48 kd retinal S-antigen (116; 99; 134), carbonic anhydrase (53; 07), a photoreceptor cell nuclear receptor (34), a 78 kd retinal protein that belongs to the “tubby” gene family (70), 35 and 40 kd photoreceptor membrane proteins (103; 101; 145), anti-paraneoplastic antigen MA2;72 and antibodies against one or more as yet unidentified retinal proteins (98; 93; 124; 139; 97; 125; 78; 40; 86).

The immunoreactivity of autoantibodies from patients with melanoma-associated retinopathy is also heterogeneous. Sera from some patients with melanoma-associated retinopathy stain a subset of approximately 30% of retinal bipolar cells and, to a lesser degree, outer rod segments (89; 143; 66; 113; 20). The molecular targets of antibipolar cell antibodies have not been well characterized (54). Other patients with melanoma-associated retinopathy have autoantibodies distinct from the “typical” antibipolar cell antibodies. Retinal antigens reacting with these antibodies include the photoreceptor proteins rhodopsin or transducin (109; 54), recoverin, enolase, S-arrestin, heat shock protein, and aldolase (80).

Epidemiology

Up to 15% of cancer patients may develop a paraneoplastic syndrome, although estimates vary widely (73). More than 75% of reported patients with paraneoplastic retinopathy have a single tumor type: small-cell lung carcinoma. A unique feature of paraneoplastic retinopathy compared to other paraneoplastic syndromes is that the second most common tumor association is with melanoma (09; 89; 71; 143; 80). Also reported are cases of patients with nonsmall-cell lung carcinoma (Guy and Aptsiauri 1960; 137; 97), breast carcinoma (72; 05), ovarian carcinoma (108; 53), endometrial carcinoma (95), prostate carcinoma (05; 103; 97; 47), gastric carcinoma (96), colon carcinoma, pancreatic cancer (44), uterine tumors (67; 27; 36; 98; 03; 124) teratoma (134), lymphoma (139), thymoma (65; 147; 97), and Waldenstrom macroglobulinemia (125). This list of associations will likely continue to evolve over time.

Additionally, with the prolonged lifespan of cancer patients and the use of immunotherapy in cancer treatment, the incidence of paraneoplastic retinopathy may be increasing. There is now an association between the use of immune checkpoint inhibitors and the development of paraneoplastic syndromes. Immune checkpoint inhibitors such as ipilimumab, pembrolizumab, and nivolumab function to enhance T-cell response to tumors and, as such, upregulate the body’s immune system. Many immune-related adverse effects have been reported, including cancer-associated retinopathy, melanoma-associated retinopathy, and paraneoplastic acute exudative polymorphous vitelliform maculopathy (24). Although initially approved for metastatic melanoma, indications for immune checkpoint inhibitors have expanded, and use will likely increase the incidence of paraneoplastic retinopathy.

Differential diagnosis

Confusing conditions

The differential diagnosis of vision loss in cancer patients is very broad and includes direct tumor spread, adverse effects of cancer treatment, and remote effects of tumors on the visual system. Magnetic resonance imaging scanning should rule out infiltration or compression of the optic nerve or chiasm by metastatic tumor. Many patients with leptomeningeal metastases from solid tumors develop vision loss during the course of their illness, either from papilledema or from direct tumor cell infiltration in and around the optic nerves (119). In some of these patients, vision loss is the presenting complaint. Metastatic disease of the retina is often unilateral and, therefore, would be atypical in the scenario of autoimmune retinopathy due to cancer.

Adverse effects of treatment. Radiation-induced retinal damage may occur following focal cobalt plaque radiotherapy for choroidal melanoma or following external beam radiotherapy for orbital tumors, usually when the doses exceed 50 Gy (22; 112). The peak time of onset of vision loss is 14 to 18 months after radiotherapy. Funduscopic exam shows “cotton wool spots,” telangiectasias, neovascularization, and in some patients, hemorrhages with neovascular glaucoma. Fluorescein angiography shows areas of retinal capillary nonperfusion.

Radiation-induced optic neuropathy most commonly occurs after fractionated radiotherapy for tumors of the orbit, paranasal sinus, nasopharynx, pituitary adenoma, or craniopharyngioma, or less commonly, following whole-brain radiotherapy for primary or metastatic brain tumors (117). Optic neuropathy may also occur after stereotactic radiosurgery for pituitary adenoma or meningioma (45). The peak incidence of radiation optic neuropathy is 12 to 18 months following completion of radiation. Patients present with painless unilateral or bilateral subacute loss of visual acuity, central scotoma, and afferent pupillary defects. Funduscopic examination may show swollen optic nerves, telangiectasias, exudates, and retinal arteriolar narrowing. MRI scanning shows patchy contrast enhancement of one or both optic nerves and occasionally of the optic chiasm. Microvascular injury is thought to be the underlying mechanism.

Several antineoplastic agents can, in rare instances, damage the retina or optic nerve and cause vision loss. Toxic retinopathy has been reported following the use of cisplatin, carboplatin, nitrosoureas, procarbazine, tamoxifen, and interferon (57; 10). Optic neuritis or optic atrophy may occur following the use of cisplatin, vincristine, fludarabine, methotrexate, nitrosoureas, procarbazine, paclitaxel, and 5-fluorouracil (82). The risk of retinal or optic nerve toxicity from chemotherapy is greatly increased when the agents (particularly cisplatin or carmustine) are administered via the internal carotid artery for treating brain tumors.

Immune checkpoint inhibition upregulates T-cell activity to target tumor cells. This upregulation of the immune system has been associated with many autoimmune side effects, including findings characteristic of autoimmune retinopathy, and cancer-associated retinopathy has been seen in the case of a patient being treated for hepatocellular carcinoma with a PD-1 inhibitor (26; 56). Uveitis is a common side effect that may cause pain, blurred vision, or floaters (114).

Other paraneoplastic ocular syndromes. Paraneoplastic optic neuritis is a rare complication of breast carcinoma, small-cell lung carcinoma, thymoma, or other tumors. Nothing is clinically distinctive about the optic neuritis in these patients, who have decreased visual acuity, afferent pupillary defects, cecocentral scotomata, and disc edema. Paraneoplastic optic neuritis may occur in isolation (76; 128; 146) or in conjunction with retinopathy (28; 40). Some patients with optic neuritis also have cerebellar ataxia (87; 30; 81; 136), multifocal encephalomyelitis (28), or a syndrome resembling neuromyelitis optica (Devic disease) (28; 11; 33; 107). Some patients have serum collapsin response-mediator protein-5 (CRMP5) antibodies, which can be associated with a variety of malignancies, including small-cell lung cancer, renal cell carcinoma, and thyroid papillary carcinoma, among others (148; 15; 92; 62). CRMP5 paraneoplastic processes can present with multiple neurologic and visual symptoms, such as cognitive dysfunction, imbalance, and blurred vision. Other patients may have anti-CV2 antibodies (30; 136; 28; 128), anti-aquaporin-4 antibodies (107), or other antineuronal antibodies (76; 11; 130).

Rarely, progressive bilateral vision loss may be caused by diffuse uveal melanocytic proliferation occurring as a remote effect of ovarian, lung, breast, gastrointestinal, or other genitourinary carcinomas (43; 31; 140). In most reported patients, vision loss was the presenting feature of an otherwise occult tumor. Fundoscopy classically reveals a pattern of multiple, round, red subretinal patches that are hyperfluorescent on fluorescein angiography. Additionally, patients have multiple pigmented and nonpigmented uveal melanocytic tumors, exudative retinal detachment, and cataracts. Other retinopathies, such as acute exudative polymorphous vitelliform maculopathy and autosomal recessive bestrophinopathy, can resemble fundoscopic findings in paraneoplastic retinopathy as well (14).

Although the above are potential causes of cancer-specific vision loss, many infectious, inflammatory, genetic, toxic, or primary ocular conditions (eg, diabetic macular edema) can lead to vision and need to be excluded with an ophthalmic fundoscopic examination. Working closely with ophthalmology (often neuro-ophthalmology, uveitis, and retina subspecialists) becomes critical to ensuring all possible etiologies are explored.

Nonparaneoplastic autoimmune retinopathy. There is increasing recognition of autoimmune retinopathy occurring in persons without an associated neoplasm (55; 42; 135). The clinical features of nonparaneoplastic autoimmune retinopathy do not reliably differ from those of cancer-associated retinopathy (also present with photopsias or blind spots and have rapid vision changes); however, visual changes can be more subtle, age of presentation can be younger, and rate of vision loss may be slower. The consensus statement on this entity concluded that essential diagnostic criteria include ERG abnormalities, an absence of fundus lesions or retinal dystrophy or other clear cause of vision loss, along with an absence of significant ocular inflammation and the presence of antiretinal antibodies on serologic testing (42). Some patients with nonparaneoplastic autoimmune retinopathy have serum autoantibodies against one or more retinal antigens, including antienolase antibodies (06; 144), or autoantibodies reacting with antigens other than recoverin or enolase (90; 104; 105; 106). Still, there remain limitations with testing for serum antiretinal antibodies as there remains no standardization or validation of testing approaches to date (41). This entity remains poorly defined.

Diagnostic workup

Although there is no single sensitive or specific diagnostic procedure, there are several ophthalmic tests that, in conjugation with the correct clinical findings and laboratory investigations, can establish a diagnosis.

Cancer-associated retinopathy. The electroretinogram in almost all patients with cancer-associated paraneoplastic retinopathy shows reduced amplitude of the a-wave, and it may be nearly flat, reflecting diffuse dysfunction of both rod and cone photoreceptor cells (137; 59). The ERG can be severely abnormal in the face of relatively preserved visual acuity and normal ophthalmoscopic examination.

Fluorescein angiography, which uses fluorescein dye to highlight the retinal vasculature, is typically normal in the early stages but can sometimes show other findings of inflammation, including vasculitis and cystoid macular edema. In late stages with retinal atrophy, window defects demonstrating retinal pigment epithelium atrophy can be seen (120).

Optical coherence tomography imaging may be the most useful in diagnosis. OCT imaging provides a detailed scan of the retinal layers and most often shows loss of the outer retina, sparing the fovea. Specifically, the photoreceptor layer is often disrupted (127).

Melanoma-associated retinopathy. The ERG in patients with melanoma-associated retinopathy usually shows a marked reduction in the amplitude of the dark-adapted b-wave and a normal dark-adapted a-wave (18; 09; 71; 143; 66; 69; 63). This resembles the abnormalities in patients with “congenital stationary night blindness” and indicates dysfunction of retinal bipolar cells. In some patients with melanoma, the ERG a-wave is reduced, reflecting photoreceptor cell degeneration (69).

Fluorescein angiography and OCT imaging may be entirely normal or show nonspecific findings. Unlike cancer-associated retinopathy, the ERG in melanoma-associated retinopathy is very specific for this entity as it identifies isolated bipolar cell dysfunction, which is only seen in melanoma-associated retinopathy or congenital stationary night blindness.

Paraneoplastic acute exudative polymorphous vitelliform maculopathy. ERG of a small number of reported patients with melanoma-associated vitelliform retinopathy suggests involvement of both rods and cones (12).

In general, a reasonable starting workup for patients with suspected paraneoplastic retinopathy includes MR imaging of the brain and orbits with contrast with attention to the optic pathways, ERG, and serum assay for antiretinal antibodies (ideally a paraneoplastic panel that includes this antibody). Screening for serum antirecoverin antibodies can be done by a number of commercial or research laboratories. Again, it should be noted that a negative assay for antirecoverin or other antiretinal antibodies does not rule out paraneoplastic retinopathy or the presence of an underlying tumor and that antiretinal antibodies have also been identified in other nonparaneoplastic entities. The presence of these antibodies is not in itself diagnostic, and there remain difficulties with antibody detection and consistency in results among different laboratories (47; 131). A study by Faez and colleagues demonstrated a concordance rate of any antiretinal antibody of around 60% and noted a poor interobserver agreement on lab detection and measurement (38). Clinical correlation remains of paramount importance.

For patients with suspected paraneoplastic retinopathy, with or without identifiable antiretinal antibodies, a complete oncologic work-up should be pursued, including CT of the chest, abdomen, or pelvis or equivalent MRI. Whole-body FDG-PET scanning may reveal a tumor in the lung or elsewhere that was not clearly imaged by other techniques (102; 52). PET scanning does have some false positives and negatives. It is not uncommon for patients’ initial evaluations for an occult tumor to be unrevealing; in these patients, the workup should be repeated every several months.

Management

In all forms of paraneoplastic retinopathy, the goal of the treatment is to eliminate the source of anti-retinal antibodies (eg, primary tumor treatment) as well as halt the antibody mediated disease process. Given the rarity of the disease, there is no well-established treatment protocol and often patients have progressive visual loss despite treatment.

When the tumor is diagnosed, it should be treated with the appropriate surgical, chemotherapeutic, or radiation measures, with the realization that progressive visual loss often occurs despite successful antitumor treatment. In conjunction with treatment of the tumor, patients with paraneoplastic retinopathy often receive corticosteroids. Intravenous methylprednisolone may result in a more favorable outcome compared to prednisone and is generally dosed around 1 mg/kg/day (60; 129). Local therapy with intravitreal or sub-Tenon triamcinolone and intravitreal long-acting steroid implants have been utilized (64; 115). In conjugation with corticosteroid treatment, PLEX for removal of the anti-retinal antibodies can prevent further photoreceptor damage (21). The most common treatment protocol is systemic corticosteroids in conjunction with PLEX, plasmapheresis, or IVIG.

Various other treatment modalities using immunomodulatory therapy have been attempted. In one series, the majority of patients with antibody-associated carcinoma-associated retinopathy or nonparaneoplastic autoimmune retinopathy showed improved visual acuity and visual fields after treatment with a regimen of prednisone, azathioprine, and cyclosporin (39). Reports exist of patients whose vision improved with intravenous immunoglobulin (51; 133) or with rituximab, a monoclonal antibody against CD20-expressing B lymphocytes (100); some of these patients failed to respond to prior corticosteroids. Significant visual improvement after treatment with the monoclonal antibody alemtuzumab, which causes depletion of T lymphocytes and B lymphocytes bearing the CD52 cell surface antigen, has been reported, but experience is limited (37).

Outcomes

Patients with cancer-associated retinopathy treated with immunosuppression therapy may show initial improvement in visual acuity, even before discovery of the underlying neoplasm, but generally, disease stabilization is the best outcome (67; 72; 116; 99; 36). Improvement in outer retinal structures, including the photoreceptor layer, has been demonstrated in a case report following chemotherapy and topical steroid drops; such structural improvement has also been demonstrated with rituximab therapy (58). There seems to be no difference in the response to prednisone between patients with antirecoverin antibodies and patients with other antiretinal antibodies or no antibodies. No definite reports mention visual improvement following surgery or chemotherapy of small-cell lung cancer without concomitant corticosteroid therapy.

Patients with melanoma-associated retinopathy generally suffer progressive vision loss despite tumor treatment or immunomodulatory therapy. Some patients do, however, have visual improvement after cytoreductive tumor surgery, corticosteroids, or intravenous immunoglobulin (09; 89; 66; 113; 20; 69; 60; 121; 138).

Although the visual prognosis may be good, patients with paraneoplastic acute exudative polymorphous vitelliform maculopathy generally have a very poor systemic prognosis as the disease is typically identified when metastatic disease has occurred, with most patients dying within months to 4 years after diagnosis (08).

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Shira S Simon MD MBA

Dr. Simon of Northwestern University has no relevant financial relationships to disclose.
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Timothy Janetos MD MBA

Dr. Janetos of Northwestern University has no relevant financial relationships to disclose.
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Nicholas J Volpe MD

Dr. Volpe of Northwestern University and Northwestern Memorial Hospital has received consulting fees from Viridian Therapeutics.
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Editor

Rimas V Lukas MD

Dr. Lukas of Northwestern University Feinberg School of Medicine received honorariums from Novartis and Novocure for speaking engagements, honorariums from Cardinal Health, Novocure, and Merck for advisory board membership, and research support from BMS as principal investigator.
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Former Authors

Edward J Dropcho MD

Patient Profile

Age range of presentation: 19 to 65+ years
Sex preponderance: male=female
Heredity: none
Population groups selectively affected: none selectively affected
Occupation groups selectively affected: none selectively affected

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Paraneoplastic retinopathy

Associated Disorders

Melanoma
Small cell lung carcinoma

Differential Diagnosis

telangiectasias
neovascular glaucoma
direct tumor spread
adverse effects of treatment
infiltration or compression of the optic nerve
- metastatic tumor
- radiation-induced retinal damage
- toxic retinopathy
- optic neuritis
- breast carcinoma
- retinitis pigmentosa
- chiasm by metastatic tumor
- macular degeneration
- leptomeningeal metastases
- pituitary tumors
- parasellar tumors
- radiation-induced optic neuropathy
- brain tumors
- swollen discs
- papilledema
- direct tumor cell infiltration
- retinal arteriolar narrowing
- afferent pupillary defects
- multifocal paraneoplastic encephalomyelitis
- microvascular injury
- disc edema
- genitourinary carcinoma
- uveal melanocytic tumors
- cataracts
- small cell lung cancer
- renal cell carcinoma
- thyroid papillary carcinoma

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Chemotherapy: neurologic complications
Common retinopathies
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Optic neuritis
Paraneoplastic syndromes
- Unusual retinopathies

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Paraneoplastic syndromes

Paraneoplastic retinopathy …

Paraneoplastic retinopathy

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Outcomes

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

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Also in This Category

Overview of neuropathology updates for infiltrating gliomas

Anti-IgLON5 disease

Anti-LGI1 encephalitis

Giant cell arteritis

Ischemic optic neuropathy

Transient visual loss

CNS germinoma

Vestibular schwannoma

Paraneoplastic retinopathy

Introduction

Overview

Key points

Historical note and terminology

Clinical manifestations

Presentation and course

Prognosis and complications

Clinical vignette

Biological basis

Etiology and pathogenesis

Epidemiology

Prevention

Differential diagnosis

Confusing conditions

Diagnostic workup

Management

Outcomes

References

Contributors

Authors

Editor

Former Authors

Patient Profile

ICD & OMIM codes

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Overview of neuropathology updates for infiltrating gliomas

Anti-IgLON5 disease

Anti-LGI1 encephalitis

Giant cell arteritis

Ischemic optic neuropathy

Transient visual loss

CNS germinoma

Vestibular schwannoma

This is an article preview.
Start a Free Account
to access the full version.