INTRODUCTION — Paraneoplastic neurologic syndromes are a heterogeneous group of neurologic disorders associated with systemic cancer and caused by mechanisms other than metastases, metabolic and nutritional deficits, infections, coagulopathy, or side effects of cancer treatment. In most cases, their pathogenesis is believed to be immune mediated.
Paraneoplastic visual syndromes are rare; they include cancer-associated retinopathy (CAR), melanoma-associated retinopathy (MAR), paraneoplastic optic neuropathy (optic neuritis; PON), and bilateral diffuse uveal melanocytic proliferation (BDUMP).
This topic discusses paraneoplastic visual syndromes. An overview of paraneoplastic syndromes and other paraneoplastic disorders are discussed separately. (See "Overview of paraneoplastic syndromes of the nervous system" and "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle" and "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis" and "Paraneoplastic cerebellar degeneration".)
CANCER-ASSOCIATED RETINOPATHY — Cancer-associated retinopathy (CAR), while rare, is probably the most common of the paraneoplastic visual syndromes.
Pathology and pathogenesis — The pathogenesis of CAR is believed to be a B cell mediated autoimmune response directed against an antigen expressed by both tumor and retina [1]. T cell responses may also play a role.
Histopathology reveals diffuse loss of inner and outer segments of the photoreceptors and loss of the outer nuclear layer with preservation of the inner nuclear layer [2]. Inflammation is variably observed.
Clinical features
Signs and symptoms — Patients with CAR develop symptoms related to dysfunction of both cones (eg, photosensitivity, abnormal visual acuity, color vision abnormalities, central scotomata) and rods (eg, nyctalopia or night blindness, prolonged dark adaptation, peripheral or ring-like scotomata). Patients typically describe photopsias along with bilateral visual dimming that progress over days to weeks. Symptoms may initially be unilateral but progress to both eyes within weeks. The triad of photosensitivity, ring scotomatous visual field loss, and attenuated retinal arteriole caliber is strongly suggestive of this disorder, although the optic fundus can appear normal in the early stages [3]. Optic disc pallor and mottling of the epithelium develop in later stages [4].
The most commonly associated tumors are small cell lung cancer (SCLC), breast cancer, gynecologic cancers, and hematologic malignancies. Less frequently, hepatocellular carcinoma, colon cancer, prostate cancer, and thymoma have been reported [4-10]. CAR precedes the cancer diagnosis in approximately one-half of patients.
Electroretinogram findings — Electroretinogram (ERG) is abnormal, with depressed a and b waves in both photopic and scotopic conditions, reflecting damage to both rods and cones. ERG is useful in the evaluation because, if abnormal, it confirms that visual loss is due to a retinopathy. In addition, specific features of the ERG results can help distinguish between CAR and melanoma-associated retinopathy (MAR). (See 'Melanoma-associated retinopathy' below.)
Antiretinal antibodies — More than half of patients with CAR have serum autoantibodies that target retinal antigens. In one cohort of patients with paraneoplastic retinopathy, 65 percent were seropositive for antiretinal antibodies, including antibodies to alpha-enolase (30 percent), transducin-alpha (17 percent), carbonic anhydrase II (14 percent), and recoverin (10 percent) (picture 1). Some of these antibodies associate with specific clinical features [5].
As these antibodies may be found in patients with systemic autoimmune disorders without visual symptoms as well as in patients with retinopathy without cancer, their presence supports an autoimmune process but does not confirm a paraneoplastic etiology. However, recoverin antibodies almost always associate with SCLC, and this helps to focus the cancer search [11]. Other antigens have been identified in patients with CAR; approximately 35 percent of patients with CAR are seronegative, suggesting that other antigens remain to be characterized [5,12].
Antirecoverin antibodies and anti-alpha-enolase antibodies have been shown to induce apoptotic death of photoreceptor cells in vitro, suggesting a direct or indirect role in the pathogenesis of the retinal degeneration [13,14].
Evaluation — Patients with unexplained vision loss with clinical or ERG evidence of rod and cone dysfunction or known or suspected malignancy should be evaluated for CAR. Testing should include measurement of serum antiretinal antibodies along with investigation for underlying neoplasm. (See "Overview of paraneoplastic syndromes of the nervous system", section on 'Search for occult malignancy'.)
Negative serum antibody titers on initial examination can become positive on subsequent testing [15]. Cerebrospinal fluid (CSF) analysis is not routinely required in the evaluation of suspected CAR. CSF may be normal or show mild lymphocytic pleocytosis and/or elevated protein.
Treatment — Traditionally, CAR has been treated with corticosteroids with anecdotal reports of mild to moderate improvement in visual function [4,16]. As with other paraneoplastic disorders, early institution of immunotherapy appears to improve the chance for treatment response [17]. Treatment of the underlying tumor does not clearly affect visual prognosis. (See "Overview of paraneoplastic syndromes of the nervous system", section on 'Treatment and prognosis'.)
There are anecdotal, uncontrolled reports of a treatment response to intravenous immune globulin (IVIG) [18], plasmapheresis [19], alemtuzumab [9], and rituximab [20]. In most patients, however, progressive visual loss and eventual blindness occur [21].
Patients treated with immune checkpoint inhibitors (ICI) have been reported as developing syndromes mimicking paraneoplastic retinopathy or optic neuropathy, including some with antiretinal antibodies [22-24]. Affected patients can have visual improvement after discontinuation of the ICI. At this time, there are no features known to distinguish symptoms due to adverse side effects of ICI from those caused by paraneoplastic mechanisms. (See "Toxicities associated with immune checkpoint inhibitors".)
MELANOMA-ASSOCIATED RETINOPATHY — Melanoma-associated retinopathy (MAR) usually presents in the setting of known melanoma, sometimes after an interval of months to years [25], although MAR may rarely precede the diagnosis of melanoma. Patients with any form of melanoma (cutaneous, choroidal, ciliary body, or choroidal nevi) may be affected, usually in the context of metastatic disease [26,27].
Clinical features — Clinical features of MAR include shimmering, flickering, or pulsating photopsias, night blindness, and loss of peripheral vision [25-28]. Color vision is preserved. The onset is usually acute and may begin in one eye. In one series, visual acuity was 20/60 or better in more than 80 percent of patients at diagnosis [25]. Vision loss progresses slowly.
Ophthalmoscopic examination is usually normal at onset, with retinal arterial attenuation seen later [2,25]. Vitreous cells are seen in a few patients. The electroretinogram (ERG) shows a characteristic pattern of a markedly reduced b wave in the presence of a normal, dark-adapted a wave, consistent with bipolar and Muller cell dysfunction. Cerebrospinal fluid (CSF) analysis is generally normal.
The sera of patients with MAR often contain antibodies that react with the bipolar cells of the retina [26,29,30]. Antibodies to arrestin, transducin, rhodopsin, and transient receptor potential channel protein 1 (TRPM1) are some of many antibodies identified [31-34]. Intravitreal injection of patient TRPM1 antibodies in mice has resulted in attenuation of the ERG b wave and uptake of the human antibodies by the retinal ON-bipolar cells, suggesting a pathogenic role in the visual symptoms [35].
Antiretinal antibodies are also prevalent (in as much as 69 percent) in patients with melanoma but no retinopathy, as well as in healthy control subjects [36,37]. The target antigens have not been determined, and the clinical significance of these antibodies is unclear [36].
Treatment and prognosis — Vision loss typically stabilizes or progresses slowly. A minority of patients improve with treatment of the tumor and/or immunotherapy, including glucocorticoids, plasma exchange, azathioprine, or intravenous immune globulin (IVIG; often at a dose of 0.4 g/kg daily for five days) [4,5,21,25,38,39]; there are no controlled studies.
OPTIC NEUROPATHY — Paraneoplastic optic neuritis (PON) has been described in a few reports, usually in association with other paraneoplastic neurologic syndromes, in particular encephalomyelitis, retinitis, and sensorimotor neuropathy [40-45]. Many of these patients harbor antibodies to collapsin-responsive mediator protein 5 (CRMP5, also called anti-CV2) [41-43,46]. However, due to the small number of patients reported, the extensive number of accompanying symptoms, and the frequent co-occurrence of other antibodies, CRMP5 antibodies should not be considered as specific or sensitive markers of PON or cancer-associated retinitis [42].
Patients typically present with painless visual loss and optic disc edema [2,42,45,47]. Both eyes are usually ultimately involved. Magnetic resonance imaging (MRI) reveals a swollen optic nerve that may mildly enhance. Fluorescein angiography can show optic disc hyperfluorescence and leakage. Vitreous cells may be prominent. Cerebrospinal fluid (CSF) may reveal a mild lymphocytic pleocytosis and/or a mildly elevated protein. Neuropathologic findings include perivascular lymphocytic infiltration and demyelination of the optic nerve [42,47].
In addition to encephalomyelitis and retinitis, other associated paraneoplastic syndromes occurring with PON include cerebellar ataxia [42,46,48-50], a Devic-like syndrome [42,43], and ophthalmoplegia [40,51]. Optic nerve dysfunction can precede, accompany, or occur after other neurologic symptoms. Some patients have PON as the only neurologic manifestation [42,47,52-55].
PON usually occurs in the setting of known cancer, but occasionally is its first manifestation [4]. SCLC is the most commonly associated cancer, but PON along with anti-CRMP5 antibodies has been described in non-small cell lung cancer [54,55], breast cancer [52], thymoma [43], renal cancer [42], and thyroid cancer [42].
Vision may improve with antitumor treatment [4,21,46]. In some reports, systemic corticosteroids are also associated with improvement, but this is not invariable; associated neurologic symptoms appear less likely to respond to treatment [21,44,53,54]. One report describes visual improvement in two cases with intravitreal triamcinolone acetonide [52].
BILATERAL DIFFUSE UVEAL MELANOCYTIC PROLIFERATION — Bilateral diffuse uveal melanocytic proliferation (BDUMP) describes a syndrome in which vision loss occurs along with diffuse bilateral proliferation of melanocytes in the uveal tract in patients with cancer. The mechanism is unknown, but does not appear to be mediated by autoimmunity.
Patients present with vision loss of varying severity [56-59]. Visual symptoms often precede cancer diagnosis; associated malignancies include ovarian, uterine, lung, and pancreatic cancers. Funduscopic examination is often normal at first presentation, but later may reveal multiple, subtle, round or oval, red patches. Fluorescein angiography reveals multifocal hyperfluorescence corresponding with these patches. Diffuse thickening of the uveal tract with elevated focal melanocytic tumors may also be seen. Optical coherence tomography reveals loss of the retinal pigment epithelium [60-62].
Bilateral retinal detachments and rapid cataract formation follow. Patients with BDUMP respond poorly if at all to surgical therapy, and most patients become blind. In limited reports, corticosteroid treatment does not appear to impact outcome [58,63]. Some patients with BDUMP treated with irradiation for presumed choroidal metastases have developed a decline in vision, but it is not clear whether progression was due to the disease process or a side effect from radiation [2]. However, one case report describes improved vision in a woman treated with external beam irradiation supplemented by drainage of subretinal fluid [59].
A serum-bound protein that stimulates melanocytic proliferation in vitro (melanocyte elongation and proliferation [CMEP] factor) was found in two patients with BDUMP [64]. Based on this finding, two patients were treated with plasmapheresis [65]. One patient had CMEP factor prior to treatment, and the other was not tested. Both patients responded with stabilization of visual function. One patient responded to intravitreal steroid implants [66].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Paraneoplastic neurologic disorders".)
SUMMARY
●Types of syndromes – Paraneoplastic visual syndromes include cancer-associated retinopathy (CAR), melanoma-associated retinopathy (MAR), paraneoplastic optic neuropathy (PON), and bilateral diffuse uveal melanocytic proliferation (BDUMP). (See 'Introduction' above.)
●Retinopathies – Immune-mediated damage to the retina occurs in two cancer-associated syndromes associated with a range of autoantibodies and underlying tumors.
•Cancer-associated retinopathy – Patients with CAR develop photosensitivity, abnormal visual acuity, color vision abnormalities, central or ring-like scotomata, and photopsias. Small cell lung cancer (SCLC) and gynecologic tumors are the most commonly associated tumors. (See 'Cancer-associated retinopathy' above.)
•Melanoma-associated retinopathy – Clinical features of MAR include shimmering, flickering, or pulsating photopsias, night blindness, and loss of peripheral vision. MAR may precede the diagnosis of melanoma. (See 'Melanoma-associated retinopathy' above.)
Treatment of CAR and MAR is usually ineffective; however, some patients improve with treatment of the tumor or immunotherapy. (See 'Cancer-associated retinopathy' above and 'Melanoma-associated retinopathy' above.)
●Paraneoplastic optic neuropathy – PON has been described in a few reports, usually in association with paraneoplastic encephalomyelitis or retinitis and SCLC. (See 'Optic neuropathy' above.)
●Uveal melanocytic proliferation – BDUMP describes a rare paraneoplastic syndrome. Visual prognosis is poor because of bilateral retinal detachment and rapid cataract formation. Survival is shortened as well, with death resulting from complications of the underlying malignancy. (See 'Bilateral diffuse uveal melanocytic proliferation' above.)
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