A Clinical Triad to Diagnose Paraneoplastic Retinopathy Daniel M. Jacobson, MD," Charles E. Thirkill, PhD,S and Stuart J. Tipping, M D t
T w o elderly men developed photosensitivity and light-induced glare, transient visual symptoms, and progressive visual loss several months before small cell carcinoma of the lung was discovered. Both patients had impaired visual acuity and color vision, ring scotomas, and attenuated retinal arteriole caliber. Electroretinography demonstrated abnormal cone and rod-mediated responses. Antiretinal antibodies were identified in their serum. Their visual sensory function improved following therapy with immunosuppressive agents. The triad of photosensitivity, ring scotomatous visual field loss, and attenuated retinal arteriole caliber should alert one to a paraneoplastic disorder affecting the retina. Jacobson DM, Thirkill CE, Tipping SJ. A clinical triad to diagnose paraneoplastic retinopathy. Ann Neurol 1770;28:162-167
Remote effects of cancer may cause visual loss by affecting structures of the anterior visual pathway through a variety of mechanisms, including toxicity from antineoplastic agents, nutritional deficiencies, and direct opportunistic infections. Visual loss may also result from an infrequently recognized paraneoplastic syndrome that causes retinal dysfunction, which is termed cancer-associated retinopatby or paraneoplatic retinopatby [1-41. Photoreceptor degeneration was demonstrated in the few reported cases that included pathological examination E5-71. W e recently evaluated 2 patients who developed visual loss from retinal dysfunction several months before small cell carcinoma of the lung was discovered. They had similar symptoms and neuroophthalmic findings, which suggested a characteristic clinical triad to diagnose paraneoplastic retinopathy ante mortem. T h e identification of antiretinal antibodies in their serum and improvement of their visual sensory function following immunosuppressive therapy support the autoimmune nature of this paraneoplastic disorder.
Patient Histories Patient 1 In early October of 1787, this 67-year-old man developed episodic, painless dimming of the central field of vision in his left eye (OS), lasting from seconds to as long as 10 minutes and occurring twice daily. Similar independent spells developed in his right eye (OD) one week later. He also noted overwhelming visual glare and photosensitivity for a few minutes when exposed to bright indoor light or sunlight. Superimposed upon these intermittent symptoms was a gradual deterioration of sight in both eyes.
From the Departments of *Neurology and Ophthalmology and the Department of +Oncology, Marshfield Clinic, Marshfield, WI, and the Department of $Ophthalmology, University of Cahfornia Davis Medical Center, Sacramento, CA.
162
On October 16, 1987, his visual acuity was 20/80 OD and 20/400 0s. Vitreous cells were noted in both eyes. Erythrocyte sedimentation rate (Westergren) was 64 mndhr. Chest radiograph and computed tomography (CT) showed right hilar and mediastinal adenopathy. H e was treated with prednisone, 80 mg daily. When he was seen four weeks later, visual acuity was 20/80 OD and 20/200 0s. The previously noted vitreous reaction had resolved. On November 30, 1987, bronchoscopy was performed following collapse of his right middle lobe which confirmed small (oat) cell carcinoma. Prednisone was discontinued. Metastatic work-up, including brain CT scan, was negative. H e received six cycles of VP-16 and cis-platinum. His vision continued to deteriorate. A second brain CT scan was normal. When Patient 1 was first evaluated at our institution on February 7, 1988, his visual acuity was 20/40 OD and counting fingers at 10 feet 0s. Photostress recovery time [ 8 ] was greater than 3 minutes OD. He correctly identified 4 of 14 pseudoisochromatic plates (Richmond Products, Boca Raton, FL) OD and none 0s. Both pupils reacted sluggishly to light, but no afferent defect was observed. Visual fields by kinetic perimetry showed extensive peripheral and midperipheral loss OD and a remaining temporal island 0s (Fig 1). Ophthalmoscopy showed mild pallor of both optic discs and abnormally thin retinal arterioles (Fig 2). His anterior chamber and vitreous were clear. The remainder of the neurological and ophthalmological examinations were normal. Abnormal laboratory values included erythrocyte sedimentation rate (Westergren) 70 mm/hr, hemoglobin 9.9 gnd dl (79 gm/L), and acute phase pattern on protein electrophoresis. Cerebrospinal fluid analysis revealed normal opening pressure, 9 leukocytesicu mm (7 x 10' leukocytes per liter), protein 44 mddl(44 gndL), IgG index 1.0, glucose 62 mddl(3.5 mmoVL), and negative studies for bacteria and
Received Nov 20, 1989, and in revised form Jan 29, 1990. Accepted for publication Feh 5 , 1990. Address correspondence to Dr Jacobson, Neuro-ophthalmology (4F),Marshfield Clinic, 1000 N . Oak Ave, Marshfield, WI 54449.
Copyright 0 1990 by the American Neurological Association
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F i g 1 . Goldmann visualjields of Patient I at the time ddiagnosis (top) showing extensive peripheral.and mid-peripheral loss. After he received prednisone for six week (bottom), his vzsual fieldsshowed mild expansion and appearance of smaller isopters.
Fig 2. Fundus photograph of the right posteriorpole of Patient I showing segmental narrowing of some of the retinal arterioles (arrowheads). The l& eye showed similar abnormalities.
fungi; cytological tests on two specimens, each containing 6 ml, were negative. Electroretinogram (ERG) showed almost flat photopic responses and severely attenuated scotopic reiponses recorded from both eyes. Normal or negative results were found for routine serum chemistry values, antinuclear antibody, fluorescent treponemal antibody, urine heavy metal assays, and bilateral temporal artery biopsies. The patient’s serum showed high reactivity with saline extracted bovine retina (Fig 3) using an enzyme-linked immunosorbent assay (ELISA) [2]. Western blot analysis of his serum reacting on bovine retina antigens 12) revealed multiple reactions (Fig 4), including strong antibody reactions with retina proteins exhibiting relative molecular weights of 48,000 and 23,000. The former protein has the migration characteristics of the retinal §-antigen {9].The latter protein was bound by antibodies from other cancer patients with visual loss [2]. H e received prednisone, 60 mg daily, and noted resolution of his episodic visual symptoms and gradual improvement of sight. On March 22, 1988, his visual acuity was 20/ 40 OD and 201200 0s. Photostress recovery time was 30 seconds OD. H e correctly identified 8 of 14 pseudoisochromatic plates OD and 5 0s. His visual fields had expanded (see Fig 1). Prednisone was gradually tapered because of intolerable side effects. When the patient was last
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seen on May 3, 1988, while receiving prednisone 10 mg daily, his visual acuity was 20130 OD and 201200 0s. Photostress recovery time O D , color vision, and visual fields were unchanged. He refused to return for further neuroophthalmological evaluations. One month after his last evaluation at our institution, he developed painful swelling of his ankles, knees, and fingers; rheumatoid factor was positive at a dilution of 1 : 10,240. He was treated with azathioprine, 300 mg daily. When contacted by telephone two months after initiation of azathioprine, he stated that his vision had improved further.
12560
Fig 3. Results of enzyme-linked immunosorbent assay showing comparative reactivity of both patients’ serum antibodies on the antigens of bovine retina. A n initial dilution of 1 :20 of each patient’s serum was progressively double diluted down eight wells and allowed to react far 1 hour at room temperature. Antibody binding toas then detected thmugh the application of goat antihuman immunoglobulil-alkalinephosphatase conjugate, reacting on para-nitro phenol. The endpoint U J S determined bli optical at 405 nm. Results are expressed graphically in log density (OD) units as the relative light absorption at 405 nm.
Fig 4. Western immunoblots of the 2 patients’ serum antibodies reacting on bovine retina antigens. Lane A , n o m l pooled human serum; lane I , Patient 1; lane 2, Patient 2. All assayed at a dilution of 1 :200. Note antibody reactions in Patient 1 with retina proteins of48 and 23 kilodultons ikdj, the migratory characteristics of the retinal S-antigen and the cancer-associated retinopathy antigen, reipectively. Patient 2 showed a strong antibody reaction with the cancer-associated retinopathy antigen.
164 Annals of Neurology Vol 28 No 2 August 1990
Patient 2 In late June of 1988, this 71-year-old man noted gradual progressive blurring of vision in his right eye. A few weeks later, a “milky white” obscuration developed in his central visual field whenever he was exposed to bright indoor light or sunlight. Dark sunglasses eliminated this obscuration. Progressive photosensitivity and overwhelming visual glare following exposure to bright light persisted and became more visually disabling. Similar symptoms developed in his left eye two months later. H e then experienced gradual loss of vision in both eyes, loss of color perception, and improvement of vision at dusk, with dim background illumination, or when he wore dark sunglasses. He also noted transient bizarre images akin to “raindrops striking a foggy window” and “flickers of flame” in his peripheral field, and expanding “ameba-shaped white objects with dark borders” obscuring his central field of vision. A chest radiograph on October 24, 1988, showed a right posterior chest mass and right perihilar adenopathy. Antinuclear antibody was positive at a dilution of 1: 1,280 (homogenous pattern). Transcutaneous needle biopsy of the right pulmonary mass suggested adenocarcinoma. He was then referred to our institution. His first neuroophthalmic evaluation on November 14, 1988, revealed visual acuities of 201200 OD and 20/50 0s. Acuity in his left eye was improved to 20140 by placing a 0.6 log unit neutral density filter in front of that eye. Photostress recovery time was 60 seconds 0s. Following 10 seconds of photostress to the right eye, his acuity curiously improved to 20180 but decayed over the next 60 seconds back to 201200. He correctly identified 1 of 14 pseudoisochromatic plates OD, and 6 0s. A small right-sided afferent pupillary defect was noted. Visual fields by kinetic perimetry showed a central and mid-peripheral ring scotoma OD, and mid-periphera1 ring scotomatous loss OS (Fig 5). Ophthalmoscopy showed normal appearing optic discs and maculas, but severely attenuated retinal arteriole caliber (Fig 6). Results of the remainder of the neurological and ophthalmological examinations were normal. Abnormal laboratory values included positive antinuclear antibody at a dilution of 1 :640 (homogenous partern) and positive anti-double-stranded D N A at a dilution of 1: 20. Cerebrospinal fluid analysis revealed normal opening pressure, no leukocytes, protein 39 mgidl(0.39 gm/L), IgG index 0.5, no oligoclonal bands, and glucose 69 m d d l (3.9 mmoV L); a 5-ml specimen submitted for cytological examination yielded no findings. ERG showed no responses under photopic or scotopic conditions in either eye. Normal or negative results were found for complete blood counts, routine serum
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Fag 5 . Goldmann tuualfields of Patient 2 at the time of daagnoszs (top) shouizng mid-perzpheral rang scotomas zn both eyes, and a central scotoma zn the right eye. After he received prednasane for six weeh (bottom), his visualfields showed generalized expansaon and reduced rzng scotomatous lo~s. chemistry values, erythrocyte sedimentation rate, complement levels, and rheumatoid factor. Positive ELISA 121 reactions were also demonstrated with his serum (see Fig 3). Westcrn blot analysis of his serum antibodies reacting on bovine retina antigens [23 demonstrated several reactions, including a strong antibody reaction with a retina protein whose molecular weight was 23,000 (see Fig 4). No evidence of antibody reactions with the 48,000-dalton retina protein was found in this patient. He received prednisone, 60 mg daily. Mediastinoscopy with biopsy of the mediastinal mass on Novembcr 17, 1988, confirmed small cell carcinoma. Staging evaluation, including head CT scan, showed no evidence of disease elsewhere. He then received three cycles of cyclophosphamide, doxombicin, and vincristine. During follow-up evaluations, he reported resolution of his transient visual symptoms and improved visual perception. His last neuroophthalmic evaluation on January 1, 1989, while he was still receiving prednisone, 60 mg daily, showed visual acuities of 201200 OD and 20/25 0s. Follow-
Fig 6.Fundm photograph Of the right posterior pole of Patient 2 showing generalized narrowing of the retinal arterioles (arrowfinding. heads). The 'eft yeshowed
Jacobson et al: Paraneoplastic Retinopathy
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ing 10 seconds of photostress to his right eye, his acuity transiently improved to 20170. Photostress recovery time was 20 seconds 0s. He correctly identified 5 of 14 pseudoisochromatic plates OD, and 7 0s. His visual fields had improved (see Fig 5). Prednisone dose was reduced because of side effects. He was admitted on February 2, 1989, for evaluation of pulmonary symptoms. Bronchoscopy showed PneumocyJtzs curinii. His condition deteriorated despite medical therapy and ventilatory support and he died on March 5, 1789. No autopsy was performed. Discussion These 2 patients demonstrated clinical and electrophysiological evidence of photoreceptor dysfunction several months before small cell carcinoma of the lung was discovered. Manifestations of cone dysfunction included light-induced glare, photosensitivity, impaired visual acuity and color vision, prolonged photostress recovery time, and abnormal photopic ERG response. Peripheral and ring scotomatous visual field loss and abnormal scotopic ERG response suggested impairment of the rod system. Their neuroophthalmic findings did not support an optic neuropathy as the cause of their visual loss. Furthermore, CT excluded compressive optic neuropathy from metastatic disease, and cerebrospinal fluid cytological studies excluded infiltrative optic neuropathy from leptomeningeal involvement. Both patients experienced visual symptoms before their cancer was treated so that chemotherapy-induced retinal toxicity was not a factor in causing their visual disorder. The clinical course and neuroophthalmic findings in these 2 patients were remarkably similar and suggested a characteristic triad to diagnose paraneoplastic retinopathy: photosensitivity, ring scotomatous visual field loss, and attenuation of retinal arteriole caliber. In the absence of meningeal irritation, cataracts, or anterior ocular segment inflammation, photosensitivity and light-induced glare are symptoms that strongly suggest acquired or congenital cone dysfunction [101. Other patients reported to have paraneoplastic retinopathy experienced transient bizarre entoptic symptoms [C;, 71 similar to our second patient, or night blindness [7, 111, suggesting symptomatic involvement of the rod system. The pattern of visual field loss in both of our patients shared characteristics similar to the defects observed in individuals with retinitis pigmentosa {121, a degenerative disorder that affects rod function. This pattern of field loss was observed in other cases of paraneoplastic retinopathy 12,4-73. The third component of the suggested triad, attenuated retinal arteriole caliber, has also been a frequent finding in other reported cases [2-5, 71. L k e the other two components of the triad, narrowed retinal vessels is a nonspecific finding that can be seen in
166 Annals of Neurology Vol 2 8 No 2 August 1790
other acquired and congenital disorders affecting the retina. When all three components of the triad are considered together, however, the diagnostic specificity of an acquired photoreceptor disorder is markedly enhanced. This is especially pertinent in individuals with known or suspected malignancies who experience visual loss, night blindness, or bizarre entoptic visual symptoms. As in our patients, about one-half of previously reported patients experienced symptoms referable to photoreceptor dysfunction several months before their underlying malignancy was discovered [a, 3, 6, 71. Small cell lung carcinoma was the most common malignancy reported in other cases of paraneoplastic retinopathy [I, 2, 4, 5 , 71. The mechanism of photoreceptor dysfunction in paraneoplastic retinopathy is incompletely understood. The few reported patients who had pathological examination showed extensive loss of photoreceptors, scattered melanophages, and minimal lymphocytic accumulation around retinal arterioles { 5-71. Retinal ganglion cells, optic nerves, and the lateral geniculate nuclei were normal in these patients [5-7}. The patient reported by Grunwald and colleagues [13} showed loss of retinal ganglion cells; atrophy of the retinal nerve fiber layer; demyelination and axonal loss of the optic nerves, chiasm, and tracts; and neuronal loss of the lateral geniculate bodies. The clinical features of their patient, like the pathological findings, suggested that optic nerve dysfunction, rather than photoreceptor dysfunction, was the cause of visual loss
~31. Evidence has accumulated supporting the role of autoimmune contnbutions to the visual loss occasionally encountered with some types of cancer C2, 4, 6, 13, 141. Keltner and colleagues [GI described their clincal and histological findings in a patient who experienced rapid loss of vision several months before cervical carcinoma was discovered. Immunohistochemistry revealed strong antibody interactions with photoreceptors when the patient’s serum was applied to sections of normal human retina. Further investigations into the antibody reactivity of this and other cancer patients’ sera, using Western blot analysis, showed a strong antibody interaction with a retina protein of 23,000 daltons [Z]. This retina antigen, referred to as the cancer-associated retinopathy antigen, was bound by antibodies from cancer patients with photoreceptor dysfunction but not by those without visual loss. Although the true nature of the 23,000-dalton cancerassociated retinopathy antigen has yet to be defined, related antibody reactions may be confined to cancer patients with photoreceptor dysfunction, since they have not yet been encountered in cancer patients with no visual disorder or in patients with other types of retinopathies, such as retinitis pigmentosa 121.
The retinal S-antigen, originally described by Wacker and colleagues 191, and more recently described in greater detail by Donoso and colleagues C151, produces extensive ocular inflammation when isolated and injected into rodents. The source of thls antigen has been traced to the photoreceptor cells, which are severely damaged by the resultant inflammation. Our first patient’s antibody reactions with this known uveitogenic retinal protein may be indicative of ongoing photoreceptor damage induced by, or accelerated by, immunological hypersensitivity to this component. Kornguth and colleagues 141 also demonstrated antiretinal antibodies in patients with paraneoplastic visual loss. Their findings differed from those of Keltner’s group because antibody reactions occurred most intensely with retinal ganglion cells 141. This group later showed that these antibodies recognized retinal and small cell lung carcinoma cell line antigens of similar molecular weight [14}. Some of the antigens shared the same molecular weights as the neurofilament triplet protein. These investigators postulated that an autoimmune response could be triggered by the release of tumor antigens into the circulation that cross react with retinal antigens C14, 161. Findings in our 2 patients provide additional support for an autoimmune mechanism of visual loss in paraneoplastic retinopathy. First, antiretinal antibodies were detected in the sera of both patients. Second, both patients experienced mild improvement of visual sensory function following therapy with immunosuppressive agents. Our first patient’s vision continued to deteriorate while he was receiving chemotherapy. Documented improvement occurred only after prednisone was initiated. Two other reported patients with paraneoplastic retinopathy showed improved vision in response to corticosteroid agents C3, 61. None of the reported patients improved during treatment solely directed at the primary malignancy; vision worsened during tumor therapy in all patients, whose case histories provided sufficient documentation of their visual status {2, 4, 5 , 7 , 141. Based on these observations, we recommend a brief trial using a corticosteroid agent in a patient with clinical and ERG evidence of photoreceptor dysfunction who has a known or suspected malignancy. We hypothesize that prednisone inhibited further immunemediated photoreceptor degeneration in our 2 patients, allowing existing cones and rods to rejuvenate, resulting in improved visual sensory function. A functional or absolute reduction in photoreceptor population caused by irreversible damage may be the reason that further expansion of their visual fields did not
occur following the initial improvement. This latter point emphasizes the need for early recognition of this syndrome. The triad of photosensitivity, ring scotomatous visual field loss, and attenuation of retinal arterioles should alert one to the possibility of this paraneoplastic disorder. The ERG can confirm the clinical suspicion of photoreceptor degeneration. Presented in part at the 114th annual meeting of the American Neurological Association, New Orleans, LA, September 24-27, 1989.
References 1. Vargas NGKZ JA, Bonilla Velasco F, Ferntindez-Terjerinap JC, Vaquero Ruano M. Degeneraci6n retiniano paraneoplbica. Medicina Clinica 1987;88:431 2. Thirkill CE, Roth AM, Keltner JL. Cancer-associated retinopathy. Arch Ophthalmol 1987;105:372-375 3. Klingele TG, Burde RM, Fbppazzo JA, et al. Paraneoplastic retinopathy. J CIin Neuro-ophthalmol 1984;4:239-245 4. Kornguth SE, Klein R, Appcn R, Choate J. Occurrence of antiretinal ganglion cell antibodies in patients with small cell carcinoma of the lung. Cancer 1982;50:1289-1293 5. Buchanan TAS, Gardiner TA, Archer DB. An ultrastructural study of retinal phocoreceptar degeneration associated with bronchial carcinoma. Am J Ophthalmol 1984;97:277-287 6. Keltner JL, Roth AM, Chang RS. Photoreceptor degeneration. Possible autoimmune disorder. Arch Ophthalmol 1983;lOl: 564-569 7. Sawyer RA, Selhorst JB, Zimmerman LE,Hoyt WF. Blindness caused by photoreceptor degeneration as a remote effect of cancer. Am J Ophthalmol 1976;81:606-613 8. Glaser JS, Savino PJ, Sumers KD, et al. The photostress recovery test in the clinical assessment of visual function. Am J Ophthalmol 1977;83:255-260 9. Wacker WB, Donoso LA, Kalsow CM, et al. Experimental allergic uveitis. Isolation, characterization, and localization of a ~ o l ~ buveitopathogenic le antigen from bovine retina. .I Immunol 1977;119:1949-1958 10. Jacobson DM, Thompson HS, Bardey JA. X-linked progressive cone dystrophy: clinical characteristics of affected males and female carriers. Ophthalmctlogy 1989;96:885-895 11. Berson EL, kssell S. Paraneoplastic night blindness with mdignant melanoma. Am J Ophthalmol 1988;106:307-311 12. Heckenlively JR, Krauss HR. Visual fields in retinitis pigmentosa. In: Heckedvely JR, ed. Retinitis pigmentosa Philadelphia: JB Lippincott Co, 1988:25-36 13. Grunwald GB, Kornguth SE, Towfghi J, et al. Autoimmune basis for visual paraneoplastic syndrome in patients with small cell Lung carcinoma. Retinal immune deposits and abkdtion of retinal ganglion cells. Cancer 1987;60:7 80-7 86 14. Grunwald GB, Klein R, Simmonds MA, Kornguth SE. Autoimmune basis for visual paraneoplastic syndrome in patients with small cell lung carcinoma. Lancet 1985;1:658-661 15. Donoso LA, Yamalu K, Merrynian CF, et al. Human S-antigen: characterization of uveitopathogenic sites. Curr Eye Res 1988;7:1077-1085 16. Kornguth SE, W n k e T, Grunwald GB, et al. Anti-neurofilament antibodies in the sera of patients with small cell carcinoma of the lung and with visual paraneoplastic syndrome. Cancer Res 1986;46:2588-2595
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T w o elderly men developed photosensitivity and light-induced glare, transient visual symptoms, and progressive visual loss several months before small cell carcinoma of the lung was discovered. Both patients had impaired visual acuity and color vision, ring scotomas, and attenuated retinal arteriole caliber. Electroretinography demonstrated abnormal cone and rod-mediated responses. Antiretinal antibodies were identified in their serum. Their visual sensory function improved following therapy with immunosuppressive agents. The triad of photosensitivity, ring scotomatous visual field loss, and attenuated retinal arteriole caliber should alert one to a paraneoplastic disorder affecting the retina. Jacobson DM, Thirkill CE, Tipping SJ. A clinical triad to diagnose paraneoplastic retinopathy. Ann Neurol 1770;28:162-167
Remote effects of cancer may cause visual loss by affecting structures of the anterior visual pathway through a variety of mechanisms, including toxicity from antineoplastic agents, nutritional deficiencies, and direct opportunistic infections. Visual loss may also result from an infrequently recognized paraneoplastic syndrome that causes retinal dysfunction, which is termed cancer-associated retinopatby or paraneoplatic retinopatby [1-41. Photoreceptor degeneration was demonstrated in the few reported cases that included pathological examination E5-71. W e recently evaluated 2 patients who developed visual loss from retinal dysfunction several months before small cell carcinoma of the lung was discovered. They had similar symptoms and neuroophthalmic findings, which suggested a characteristic clinical triad to diagnose paraneoplastic retinopathy ante mortem. T h e identification of antiretinal antibodies in their serum and improvement of their visual sensory function following immunosuppressive therapy support the autoimmune nature of this paraneoplastic disorder.
Patient Histories Patient 1 In early October of 1787, this 67-year-old man developed episodic, painless dimming of the central field of vision in his left eye (OS), lasting from seconds to as long as 10 minutes and occurring twice daily. Similar independent spells developed in his right eye (OD) one week later. He also noted overwhelming visual glare and photosensitivity for a few minutes when exposed to bright indoor light or sunlight. Superimposed upon these intermittent symptoms was a gradual deterioration of sight in both eyes.
From the Departments of *Neurology and Ophthalmology and the Department of +Oncology, Marshfield Clinic, Marshfield, WI, and the Department of $Ophthalmology, University of Cahfornia Davis Medical Center, Sacramento, CA.
162
On October 16, 1987, his visual acuity was 20/80 OD and 20/400 0s. Vitreous cells were noted in both eyes. Erythrocyte sedimentation rate (Westergren) was 64 mndhr. Chest radiograph and computed tomography (CT) showed right hilar and mediastinal adenopathy. H e was treated with prednisone, 80 mg daily. When he was seen four weeks later, visual acuity was 20/80 OD and 20/200 0s. The previously noted vitreous reaction had resolved. On November 30, 1987, bronchoscopy was performed following collapse of his right middle lobe which confirmed small (oat) cell carcinoma. Prednisone was discontinued. Metastatic work-up, including brain CT scan, was negative. H e received six cycles of VP-16 and cis-platinum. His vision continued to deteriorate. A second brain CT scan was normal. When Patient 1 was first evaluated at our institution on February 7, 1988, his visual acuity was 20/40 OD and counting fingers at 10 feet 0s. Photostress recovery time [ 8 ] was greater than 3 minutes OD. He correctly identified 4 of 14 pseudoisochromatic plates (Richmond Products, Boca Raton, FL) OD and none 0s. Both pupils reacted sluggishly to light, but no afferent defect was observed. Visual fields by kinetic perimetry showed extensive peripheral and midperipheral loss OD and a remaining temporal island 0s (Fig 1). Ophthalmoscopy showed mild pallor of both optic discs and abnormally thin retinal arterioles (Fig 2). His anterior chamber and vitreous were clear. The remainder of the neurological and ophthalmological examinations were normal. Abnormal laboratory values included erythrocyte sedimentation rate (Westergren) 70 mm/hr, hemoglobin 9.9 gnd dl (79 gm/L), and acute phase pattern on protein electrophoresis. Cerebrospinal fluid analysis revealed normal opening pressure, 9 leukocytesicu mm (7 x 10' leukocytes per liter), protein 44 mddl(44 gndL), IgG index 1.0, glucose 62 mddl(3.5 mmoVL), and negative studies for bacteria and
Received Nov 20, 1989, and in revised form Jan 29, 1990. Accepted for publication Feh 5 , 1990. Address correspondence to Dr Jacobson, Neuro-ophthalmology (4F),Marshfield Clinic, 1000 N . Oak Ave, Marshfield, WI 54449.
Copyright 0 1990 by the American Neurological Association
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F i g 1 . Goldmann visualjields of Patient I at the time ddiagnosis (top) showing extensive peripheral.and mid-peripheral loss. After he received prednisone for six week (bottom), his vzsual fieldsshowed mild expansion and appearance of smaller isopters.
Fig 2. Fundus photograph of the right posteriorpole of Patient I showing segmental narrowing of some of the retinal arterioles (arrowheads). The l& eye showed similar abnormalities.
fungi; cytological tests on two specimens, each containing 6 ml, were negative. Electroretinogram (ERG) showed almost flat photopic responses and severely attenuated scotopic reiponses recorded from both eyes. Normal or negative results were found for routine serum chemistry values, antinuclear antibody, fluorescent treponemal antibody, urine heavy metal assays, and bilateral temporal artery biopsies. The patient’s serum showed high reactivity with saline extracted bovine retina (Fig 3) using an enzyme-linked immunosorbent assay (ELISA) [2]. Western blot analysis of his serum reacting on bovine retina antigens 12) revealed multiple reactions (Fig 4), including strong antibody reactions with retina proteins exhibiting relative molecular weights of 48,000 and 23,000. The former protein has the migration characteristics of the retinal §-antigen {9].The latter protein was bound by antibodies from other cancer patients with visual loss [2]. H e received prednisone, 60 mg daily, and noted resolution of his episodic visual symptoms and gradual improvement of sight. On March 22, 1988, his visual acuity was 20/ 40 OD and 201200 0s. Photostress recovery time was 30 seconds OD. H e correctly identified 8 of 14 pseudoisochromatic plates OD and 5 0s. His visual fields had expanded (see Fig 1). Prednisone was gradually tapered because of intolerable side effects. When the patient was last
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seen on May 3, 1988, while receiving prednisone 10 mg daily, his visual acuity was 20130 OD and 201200 0s. Photostress recovery time O D , color vision, and visual fields were unchanged. He refused to return for further neuroophthalmological evaluations. One month after his last evaluation at our institution, he developed painful swelling of his ankles, knees, and fingers; rheumatoid factor was positive at a dilution of 1 : 10,240. He was treated with azathioprine, 300 mg daily. When contacted by telephone two months after initiation of azathioprine, he stated that his vision had improved further.
12560
Fig 3. Results of enzyme-linked immunosorbent assay showing comparative reactivity of both patients’ serum antibodies on the antigens of bovine retina. A n initial dilution of 1 :20 of each patient’s serum was progressively double diluted down eight wells and allowed to react far 1 hour at room temperature. Antibody binding toas then detected thmugh the application of goat antihuman immunoglobulil-alkalinephosphatase conjugate, reacting on para-nitro phenol. The endpoint U J S determined bli optical at 405 nm. Results are expressed graphically in log density (OD) units as the relative light absorption at 405 nm.
Fig 4. Western immunoblots of the 2 patients’ serum antibodies reacting on bovine retina antigens. Lane A , n o m l pooled human serum; lane I , Patient 1; lane 2, Patient 2. All assayed at a dilution of 1 :200. Note antibody reactions in Patient 1 with retina proteins of48 and 23 kilodultons ikdj, the migratory characteristics of the retinal S-antigen and the cancer-associated retinopathy antigen, reipectively. Patient 2 showed a strong antibody reaction with the cancer-associated retinopathy antigen.
164 Annals of Neurology Vol 28 No 2 August 1990
Patient 2 In late June of 1988, this 71-year-old man noted gradual progressive blurring of vision in his right eye. A few weeks later, a “milky white” obscuration developed in his central visual field whenever he was exposed to bright indoor light or sunlight. Dark sunglasses eliminated this obscuration. Progressive photosensitivity and overwhelming visual glare following exposure to bright light persisted and became more visually disabling. Similar symptoms developed in his left eye two months later. H e then experienced gradual loss of vision in both eyes, loss of color perception, and improvement of vision at dusk, with dim background illumination, or when he wore dark sunglasses. He also noted transient bizarre images akin to “raindrops striking a foggy window” and “flickers of flame” in his peripheral field, and expanding “ameba-shaped white objects with dark borders” obscuring his central field of vision. A chest radiograph on October 24, 1988, showed a right posterior chest mass and right perihilar adenopathy. Antinuclear antibody was positive at a dilution of 1: 1,280 (homogenous pattern). Transcutaneous needle biopsy of the right pulmonary mass suggested adenocarcinoma. He was then referred to our institution. His first neuroophthalmic evaluation on November 14, 1988, revealed visual acuities of 201200 OD and 20/50 0s. Acuity in his left eye was improved to 20140 by placing a 0.6 log unit neutral density filter in front of that eye. Photostress recovery time was 60 seconds 0s. Following 10 seconds of photostress to the right eye, his acuity curiously improved to 20180 but decayed over the next 60 seconds back to 201200. He correctly identified 1 of 14 pseudoisochromatic plates OD, and 6 0s. A small right-sided afferent pupillary defect was noted. Visual fields by kinetic perimetry showed a central and mid-peripheral ring scotoma OD, and mid-periphera1 ring scotomatous loss OS (Fig 5). Ophthalmoscopy showed normal appearing optic discs and maculas, but severely attenuated retinal arteriole caliber (Fig 6). Results of the remainder of the neurological and ophthalmological examinations were normal. Abnormal laboratory values included positive antinuclear antibody at a dilution of 1 :640 (homogenous partern) and positive anti-double-stranded D N A at a dilution of 1: 20. Cerebrospinal fluid analysis revealed normal opening pressure, no leukocytes, protein 39 mgidl(0.39 gm/L), IgG index 0.5, no oligoclonal bands, and glucose 69 m d d l (3.9 mmoV L); a 5-ml specimen submitted for cytological examination yielded no findings. ERG showed no responses under photopic or scotopic conditions in either eye. Normal or negative results were found for complete blood counts, routine serum
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Ill0
RIGHT
Fag 5 . Goldmann tuualfields of Patient 2 at the time of daagnoszs (top) shouizng mid-perzpheral rang scotomas zn both eyes, and a central scotoma zn the right eye. After he received prednasane for six weeh (bottom), his visualfields showed generalized expansaon and reduced rzng scotomatous lo~s. chemistry values, erythrocyte sedimentation rate, complement levels, and rheumatoid factor. Positive ELISA 121 reactions were also demonstrated with his serum (see Fig 3). Westcrn blot analysis of his serum antibodies reacting on bovine retina antigens [23 demonstrated several reactions, including a strong antibody reaction with a retina protein whose molecular weight was 23,000 (see Fig 4). No evidence of antibody reactions with the 48,000-dalton retina protein was found in this patient. He received prednisone, 60 mg daily. Mediastinoscopy with biopsy of the mediastinal mass on Novembcr 17, 1988, confirmed small cell carcinoma. Staging evaluation, including head CT scan, showed no evidence of disease elsewhere. He then received three cycles of cyclophosphamide, doxombicin, and vincristine. During follow-up evaluations, he reported resolution of his transient visual symptoms and improved visual perception. His last neuroophthalmic evaluation on January 1, 1989, while he was still receiving prednisone, 60 mg daily, showed visual acuities of 201200 OD and 20/25 0s. Follow-
Fig 6.Fundm photograph Of the right posterior pole of Patient 2 showing generalized narrowing of the retinal arterioles (arrowfinding. heads). The 'eft yeshowed
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ing 10 seconds of photostress to his right eye, his acuity transiently improved to 20170. Photostress recovery time was 20 seconds 0s. He correctly identified 5 of 14 pseudoisochromatic plates OD, and 7 0s. His visual fields had improved (see Fig 5). Prednisone dose was reduced because of side effects. He was admitted on February 2, 1989, for evaluation of pulmonary symptoms. Bronchoscopy showed PneumocyJtzs curinii. His condition deteriorated despite medical therapy and ventilatory support and he died on March 5, 1789. No autopsy was performed. Discussion These 2 patients demonstrated clinical and electrophysiological evidence of photoreceptor dysfunction several months before small cell carcinoma of the lung was discovered. Manifestations of cone dysfunction included light-induced glare, photosensitivity, impaired visual acuity and color vision, prolonged photostress recovery time, and abnormal photopic ERG response. Peripheral and ring scotomatous visual field loss and abnormal scotopic ERG response suggested impairment of the rod system. Their neuroophthalmic findings did not support an optic neuropathy as the cause of their visual loss. Furthermore, CT excluded compressive optic neuropathy from metastatic disease, and cerebrospinal fluid cytological studies excluded infiltrative optic neuropathy from leptomeningeal involvement. Both patients experienced visual symptoms before their cancer was treated so that chemotherapy-induced retinal toxicity was not a factor in causing their visual disorder. The clinical course and neuroophthalmic findings in these 2 patients were remarkably similar and suggested a characteristic triad to diagnose paraneoplastic retinopathy: photosensitivity, ring scotomatous visual field loss, and attenuation of retinal arteriole caliber. In the absence of meningeal irritation, cataracts, or anterior ocular segment inflammation, photosensitivity and light-induced glare are symptoms that strongly suggest acquired or congenital cone dysfunction [101. Other patients reported to have paraneoplastic retinopathy experienced transient bizarre entoptic symptoms [C;, 71 similar to our second patient, or night blindness [7, 111, suggesting symptomatic involvement of the rod system. The pattern of visual field loss in both of our patients shared characteristics similar to the defects observed in individuals with retinitis pigmentosa {121, a degenerative disorder that affects rod function. This pattern of field loss was observed in other cases of paraneoplastic retinopathy 12,4-73. The third component of the suggested triad, attenuated retinal arteriole caliber, has also been a frequent finding in other reported cases [2-5, 71. L k e the other two components of the triad, narrowed retinal vessels is a nonspecific finding that can be seen in
166 Annals of Neurology Vol 2 8 No 2 August 1790
other acquired and congenital disorders affecting the retina. When all three components of the triad are considered together, however, the diagnostic specificity of an acquired photoreceptor disorder is markedly enhanced. This is especially pertinent in individuals with known or suspected malignancies who experience visual loss, night blindness, or bizarre entoptic visual symptoms. As in our patients, about one-half of previously reported patients experienced symptoms referable to photoreceptor dysfunction several months before their underlying malignancy was discovered [a, 3, 6, 71. Small cell lung carcinoma was the most common malignancy reported in other cases of paraneoplastic retinopathy [I, 2, 4, 5 , 71. The mechanism of photoreceptor dysfunction in paraneoplastic retinopathy is incompletely understood. The few reported patients who had pathological examination showed extensive loss of photoreceptors, scattered melanophages, and minimal lymphocytic accumulation around retinal arterioles { 5-71. Retinal ganglion cells, optic nerves, and the lateral geniculate nuclei were normal in these patients [5-7}. The patient reported by Grunwald and colleagues [13} showed loss of retinal ganglion cells; atrophy of the retinal nerve fiber layer; demyelination and axonal loss of the optic nerves, chiasm, and tracts; and neuronal loss of the lateral geniculate bodies. The clinical features of their patient, like the pathological findings, suggested that optic nerve dysfunction, rather than photoreceptor dysfunction, was the cause of visual loss
~31. Evidence has accumulated supporting the role of autoimmune contnbutions to the visual loss occasionally encountered with some types of cancer C2, 4, 6, 13, 141. Keltner and colleagues [GI described their clincal and histological findings in a patient who experienced rapid loss of vision several months before cervical carcinoma was discovered. Immunohistochemistry revealed strong antibody interactions with photoreceptors when the patient’s serum was applied to sections of normal human retina. Further investigations into the antibody reactivity of this and other cancer patients’ sera, using Western blot analysis, showed a strong antibody interaction with a retina protein of 23,000 daltons [Z]. This retina antigen, referred to as the cancer-associated retinopathy antigen, was bound by antibodies from cancer patients with photoreceptor dysfunction but not by those without visual loss. Although the true nature of the 23,000-dalton cancerassociated retinopathy antigen has yet to be defined, related antibody reactions may be confined to cancer patients with photoreceptor dysfunction, since they have not yet been encountered in cancer patients with no visual disorder or in patients with other types of retinopathies, such as retinitis pigmentosa 121.
The retinal S-antigen, originally described by Wacker and colleagues 191, and more recently described in greater detail by Donoso and colleagues C151, produces extensive ocular inflammation when isolated and injected into rodents. The source of thls antigen has been traced to the photoreceptor cells, which are severely damaged by the resultant inflammation. Our first patient’s antibody reactions with this known uveitogenic retinal protein may be indicative of ongoing photoreceptor damage induced by, or accelerated by, immunological hypersensitivity to this component. Kornguth and colleagues 141 also demonstrated antiretinal antibodies in patients with paraneoplastic visual loss. Their findings differed from those of Keltner’s group because antibody reactions occurred most intensely with retinal ganglion cells 141. This group later showed that these antibodies recognized retinal and small cell lung carcinoma cell line antigens of similar molecular weight [14}. Some of the antigens shared the same molecular weights as the neurofilament triplet protein. These investigators postulated that an autoimmune response could be triggered by the release of tumor antigens into the circulation that cross react with retinal antigens C14, 161. Findings in our 2 patients provide additional support for an autoimmune mechanism of visual loss in paraneoplastic retinopathy. First, antiretinal antibodies were detected in the sera of both patients. Second, both patients experienced mild improvement of visual sensory function following therapy with immunosuppressive agents. Our first patient’s vision continued to deteriorate while he was receiving chemotherapy. Documented improvement occurred only after prednisone was initiated. Two other reported patients with paraneoplastic retinopathy showed improved vision in response to corticosteroid agents C3, 61. None of the reported patients improved during treatment solely directed at the primary malignancy; vision worsened during tumor therapy in all patients, whose case histories provided sufficient documentation of their visual status {2, 4, 5 , 7 , 141. Based on these observations, we recommend a brief trial using a corticosteroid agent in a patient with clinical and ERG evidence of photoreceptor dysfunction who has a known or suspected malignancy. We hypothesize that prednisone inhibited further immunemediated photoreceptor degeneration in our 2 patients, allowing existing cones and rods to rejuvenate, resulting in improved visual sensory function. A functional or absolute reduction in photoreceptor population caused by irreversible damage may be the reason that further expansion of their visual fields did not
occur following the initial improvement. This latter point emphasizes the need for early recognition of this syndrome. The triad of photosensitivity, ring scotomatous visual field loss, and attenuation of retinal arterioles should alert one to the possibility of this paraneoplastic disorder. The ERG can confirm the clinical suspicion of photoreceptor degeneration. Presented in part at the 114th annual meeting of the American Neurological Association, New Orleans, LA, September 24-27, 1989.
References 1. Vargas NGKZ JA, Bonilla Velasco F, Ferntindez-Terjerinap JC, Vaquero Ruano M. Degeneraci6n retiniano paraneoplbica. Medicina Clinica 1987;88:431 2. Thirkill CE, Roth AM, Keltner JL. Cancer-associated retinopathy. Arch Ophthalmol 1987;105:372-375 3. Klingele TG, Burde RM, Fbppazzo JA, et al. Paraneoplastic retinopathy. J CIin Neuro-ophthalmol 1984;4:239-245 4. Kornguth SE, Klein R, Appcn R, Choate J. Occurrence of antiretinal ganglion cell antibodies in patients with small cell carcinoma of the lung. Cancer 1982;50:1289-1293 5. Buchanan TAS, Gardiner TA, Archer DB. An ultrastructural study of retinal phocoreceptar degeneration associated with bronchial carcinoma. Am J Ophthalmol 1984;97:277-287 6. Keltner JL, Roth AM, Chang RS. Photoreceptor degeneration. Possible autoimmune disorder. Arch Ophthalmol 1983;lOl: 564-569 7. Sawyer RA, Selhorst JB, Zimmerman LE,Hoyt WF. Blindness caused by photoreceptor degeneration as a remote effect of cancer. Am J Ophthalmol 1976;81:606-613 8. Glaser JS, Savino PJ, Sumers KD, et al. The photostress recovery test in the clinical assessment of visual function. Am J Ophthalmol 1977;83:255-260 9. Wacker WB, Donoso LA, Kalsow CM, et al. Experimental allergic uveitis. Isolation, characterization, and localization of a ~ o l ~ buveitopathogenic le antigen from bovine retina. .I Immunol 1977;119:1949-1958 10. Jacobson DM, Thompson HS, Bardey JA. X-linked progressive cone dystrophy: clinical characteristics of affected males and female carriers. Ophthalmctlogy 1989;96:885-895 11. Berson EL, kssell S. Paraneoplastic night blindness with mdignant melanoma. Am J Ophthalmol 1988;106:307-311 12. Heckenlively JR, Krauss HR. Visual fields in retinitis pigmentosa. In: Heckedvely JR, ed. Retinitis pigmentosa Philadelphia: JB Lippincott Co, 1988:25-36 13. Grunwald GB, Kornguth SE, Towfghi J, et al. Autoimmune basis for visual paraneoplastic syndrome in patients with small cell Lung carcinoma. Retinal immune deposits and abkdtion of retinal ganglion cells. Cancer 1987;60:7 80-7 86 14. Grunwald GB, Klein R, Simmonds MA, Kornguth SE. Autoimmune basis for visual paraneoplastic syndrome in patients with small cell lung carcinoma. Lancet 1985;1:658-661 15. Donoso LA, Yamalu K, Merrynian CF, et al. Human S-antigen: characterization of uveitopathogenic sites. Curr Eye Res 1988;7:1077-1085 16. Kornguth SE, W n k e T, Grunwald GB, et al. Anti-neurofilament antibodies in the sera of patients with small cell carcinoma of the lung and with visual paraneoplastic syndrome. Cancer Res 1986;46:2588-2595
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