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Pareneoplastic Afferent Visual Syndromes in Neuro-ophthalmology
Andrew G. Lee, MD
The University of Iowa Hospitals and Clinics · Iowa City, IAIntroduction
Cancer produces neuro-ophthalmic manifestations through a variety of mechanisms including direct compressive effects from the primary lesion or metastatic disease, infiltration (e.g., carcinomatous or lymphomatous meningitis), indirect effects of treatment (e.g., chemotherapy or radiation side effects) or remote effects of the cancer (e.g., paraneoplastic effect). Paraneoplastic disease may present with afferent (visual loss or photopsias) or efferent (diplopia or oscillopsia) symptoms. This tutorial reviews the paraneoplastic afferent syndromes of significance to ophthalmologists.
Paraneoplastic Afferent Disease
The main forms of paraneoplastic afferent disease are cancer-associated retinopathy (CAR),1-4 melanoma-associated retinopathy (MAR),5,6 cancer-associated cone dysfunction, bilateral diffuse uveal melanocytic proliferation (bDUMP) and paraneoplastic optic neuropathy. Non-cancer-related autoimmune-mediated retinopathies may present in a similar fashion to these paraneoplastic disorders but are not discussed in this tutorial.
Cancer-Associated Retinopathy
Symptoms of CAR
Patients with CAR typically present with subacute, bilateral and symmetric, but progressive, painless vision loss. Unilateral or asymmetric onset may occur, but usually sequential bilateral disease ensues over the following few weeks to months. Often, a complaint of photopsias (e.g., flashing lights or positive visual phenomenon) exists that implicates retinal dysfunction.1-17 Cone dysfunction in CAR produces the symptoms of photopsia, photosensitivity, glare after light exposure (hemeralopia), reduced visual acuity, visual field loss and dyschromatopsia. This differs from the presentation of melanoma associated retinopathy (described below).6 Rod dysfunction produces symptoms of night blindness, impaired dark adaptation and peripheral visual field loss. Some patients have predominant or only cone dysfunction as their paraneoplastic effect.
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Signs of CAR
The visual acuity is usually decreased and the visual field may show paracentral or ring scotomas (Slide 1). Additionally, color vision is often impaired. The ophthalmoscopic examination may be normal or near normal, especially early in the course of the disease. A prolonged macular photostress test time (i.e., testing and retesting visual acuity before and after a bright light stimulus) may implicate a retinal origin to the visual loss. Vitreous cells are present and eventually retinal pigment epithelial derangement, arteriolar narrowing and optic atrophy develop.5-6
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Diagnostic testing
The multifocal and full-field electroretinogram (ERG) are typically abnormal (especially for cone function) in CAR and can become extinguished (Slide 2). Fluorescein angiography may be normal, especially when the fundus examination is normal, but may show abnormalities in the retinal pigment epithelium (RPE) or retinal vasculature over time. Laboratory testing with specific immunofluorescence techniques can identify circulating paraneoplastic retinal antibodies (e.g., 23-kDa [recoverin], 46-kDa [enolase], 45-kDa, 50-kDa [cone dysfunction] and 60-kDa proteins). Cerebrospinal fluid (CSF) analysis may show elevated CSF protein or cells.5-6,16-17
The visual loss in CAR precedes the diagnosis of the underlying malignancy. A full medical examination (e.g., internist or oncologist with gynecologic and breast examination) and an evaluation for cancer (e.g., imaging of the entire body, stool guaiac, mammogram, etc.) are indicated in CAR. The cancers that are most frequently associated with CAR are small-cell lung cancer, gynecologic cancer and breast cancer; however, other malignancies have been reported (e.g., other forms of lung cancer, lymphoma, and pancreatic, prostate, bladder, laryngeal or colon cancers).5-6
Treatment
Treatment of the underlying neoplasm does not improve the visual outcome. Although multiple immunosuppressive regimens have been used, no proven effective therapy for CAR exists. Plasmapheresis with steroids has improved vision in at least one anecdotal case. The prognosis is generally poor for patients with CAR.
Melanoma-Associated Retinopathy
Symptoms of MAR
Unlike CAR, where the retinopathy often precedes the diagnosis of cancer, patients with MAR usually already carry the diagnosis of melanoma.18-22 The ocular symptoms and signs of both CAR and MAR are due to the specific retinal elements that are affected. MAR usually only affects the rods (as opposed to CAR, which affects both rods and cones). The rod dysfunction produces symptoms of difficulty with night vision or dim illumination (nyctalopia), prolonged dark adaptation and peripheral rather than central visual field loss. Like CAR, patients with MAR often report photopsias (e.g., positive visual phenomena, flashing or flickering lights, smoky or swirling vision). Patients with MAR for uncertain reasons are predominantly men.
Signs of MAR
In contrast to patients with CAR (who have loss of central vision and visual field), patients with MAR have normal or near-normal visual acuity, relatively preserved color vision, central visual fields and a normal fundus. Peripheral or mid-peripheral visual field loss develops over time, and Goldmann testing or other peripheral field perimetry may be superior to central visual field testing (eg, automated central 24° or 30° testing). Keltner and colleagues reported 34 patients with MAR and 28 patients (82%) had initial visual acuity of 20/60 or better. Perimetry showed generalized constriction in 18 (67%) of 27 patients and 18 (67%) of 27 patients had central or paracentral scotomas. The visual acuity decreases over time, however, and only 10 patients had visual acuity of better than 20/60 at their last follow-up examination.6
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As in CAR, the fundus is often normal at presentation, but arteriolar narrowing (Slide 3 and Slide 4), RPE changes and vitreous cells eventually appear. Keltner and colleagues reported that, in 43 patients with MAR, 19 patients (44%) had a normal fundus at onset, 13 patients (30%) had vascular attenuation, and 12 patients (28%) had RPE changes. Vitreous cells were present in 13 patients (30%) and 10 patients (23%) had optic-disc pallor.6
Evaluation
The fluorescein angiography appears normal; however, over time, it may demonstrate mild peripheral vascular leakage. The ERG in MAR shows a markedly reduced or absent dark-adapted b-wave (bipolar and Müller cell dysfunction) with preservation of the wave. Multifocal ERG (MERG) is useful for patients with localized or paracentral visual field loss. Interestingly, the ERG in MAR is similar to the ERG pattern of congenital stationary night blindness. The diagnosis of melanoma is known months to years before the diagnosis of MAR. Antiretinal antibody testing is performed for MAR as well as CAR.6
Treatment and prognosis
As with CAR, the treatment of MAR remains elusive, although immunosuppressive regimens have been tried (e.g., corticosteroids, IVIg, plasmapheresis). Unlike those with CAR, however, patients with MAR may have a stable visual course.6
Bilateral Diffuse Uveal Melanocytic Proliferation
bDUMP is a rare form of paraneoplastic afferent disease. The classic signs are multifocal, round subretinal patches of abnormal posterior pole RPE. The fluorescein angiography shows hyperfluorescence in these areas. Multiple, pigmented and nonpigmented, elevated uveal melanocytic tumors associated with diffuse thickening of the uveal tract with exudative retinal detachments and progressive cataracts exist. Dilated episcleral veins, shallow anterior chamber, pigmented anterior and posterior segment cells, pigmented keratitic precipitates and glaucoma may also be included. The most common neoplasm in women is ovarian or uterine cancer, whereas in men, the most common is lung cancer. The pathogenesis is unknown and the visual and systemic prognosis is poor despite treatment of the underlying neoplasm and immunosuppression.23
Paraneoplastic Optic Neuropathy
Symptoms
Paraneoplastic optic neuropathy (PON) is less common than paraneoplastic retinopathy. Visual symptoms, like those associated with CAR, often precede the diagnosis of the underlying malignancy and the most common neoplasm is small-cell carcinoma. The optic neuropathy is progressive over weeks to months and is bilateral and symmetric.24-26
Signs
Visual field and visual acuity loss are the predominant findings. An afferent pupillary defect may be present in bilateral but asymmetric cases. Optic disc edema and optic atrophy develop. Some patients with PON have a concomitant paraneoplastic retinopathy.24-26
Evaluation
Neuroimaging is usually normal in PON. Cerebrospinal fluid (CSF) analysis may show elevated CSF protein and CSF cell counts, but carcinomatous meningitis should be excluded in such patients (e.g., CSF cytology). Paraneoplastic antibodies have been reported in PON including 60 kDa, anti-CV2, anti-retinal ganglion cell antibodies and 66-kDa proteins. The collapsin response-mediated protein (CRMP-5) has been implicated in patients with optic neuropathy, retinopathy and cerebellar syndrome. Patients with an unexplained optic neuropathy and cerebellar ataxia should especially be considered for evaluation for PON (CRMP-5). Most patients with PON have small-cell lung carcinoma; however, some patients have other tumors (e.g., thymoma). Cross and colleagues reported 16 patients (ages 52-74) with CRMP-5-IgG and optic neuropathy. All patients were smokers and nine were women. Coexisting retinitis was noted in five patients and no patients had CAR antibody IgG. Fifteen patients had subacute vision loss with swollen optic discs and visual field defects. All five patients who had coexisting retinitis who were tested had an abnormal ERG. Nine patients had vitreous cells and, at vitrectomy, showed reactive lymphocytosis.
The Mayo Clinic neuroimmunology laboratory detected CRMP-5-IgG in 121 of 68,000 patients with subacute suspected paraneoplastic neurologic syndromes. The Mayo Clinic report concluded that CRMP-5 autoantibody was as frequent as PCA-1 (anti-Yo) autoantibody and second only to ANNA-1 (anti-Hu). Clinical information was available for 116 of the 121 Mayo Clinic patients and revealed multifocal neurological signs including: chorea (11%), cranial neuropathy (17%), disturbances of olfaction/taste (10%), optic neuropathy (7%), peripheral neuropathy (47%), autonomic neuropathy (31%), cerebellar ataxia (26%), subacute dementia (25%) and neuromuscular junction disorders (12%). The treatment of PON, as with CAR, has been of marginal benefit.24
Conclusion
Paraneoplastic visual loss is uncommon. Ophthalmologists should be aware of the diagnosis of paraneoplastic retinopathy and optic neuropathy. Patients with unexplained and progressive visual loss, photopsias and ring scotomas must be evaluated for CAR. Patients with melanoma who present with visual loss - especially unexplained peripheral or midperipheral visual field loss - should be evaluated for MAR. Electroretinography is diagnostic and specific paraneoplastic antibodies can be detected. Although treatment is limited, immunosuppressive therapy may stabilize the visual loss. Paraneoplastic optic neuropathy is rare, but should be in the differential diagnosis of unexplained bilateral optic neuropathy. The presence of ataxia, vitreous cells and concomitant retinitis might suggest the diagnosis of CRMP-5 related optic neuropathy. Paraneoplastic antibodies should be performed and a search undertaken for an occult malignancy (often lung cancer) in these patients.
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