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Show J. Clill, Nellro-ophthalmol. 4: 239-245, 1984, Paraneoplastic Retinopathy TERENCE G, KLINGELE, M,D, RONALD M. BURDE, M.D. J. ALAN RAPPAZZO, M.D. MICHAEL J. ISSERMAN, M.D. DEAN BURGESS, M.D. OWEN KANTOR, M.D. Abstract Paraneop1astic retinopathy appears to represent a nonmetastatic remote effect of carcinoma and is characterized by rapid visual deterioration accompanied by narrow arterioles seen on ophthalmoscopic examination and an extinguished electroretinogram. This syndrome has been described in postmenopausal women, and it is possible that it represents an autoimmune disorder. Corticosteroid therapy may arrest the visual deterioration. The nonmetastatic, remote effects of cancer on the nervous system are well known (Table 1), and include a variety of focal degenerative or inflammatory processes including cerebellar degeneration, brain stem encephalitis, motor neuron degeneration, peripheral neuropathy, polymyositis, and myasthenic syndromes, Many of these processes appear to be immunologically mediated1 - n A somewhat similar degenerative phenomenon involving the retina is described in detail by Sawyer et al 7 Their cases have diminished acuity, photopsia, ring-like scotomas, and nyctalopia, Sometimes the symptoms precede the diagnosis of malignancy by several months. Pathologically in three cases, they note severe degeneration of photoreceptors, loss of the outer nuclear layer, and melanophagic activity in the retina, Keltner et aL" report a similar case in which a 61-yearold white female initially notes photopsia and floaters and then diminishing acuity which appears to improve on oral prednisone therapy. Her workup includes an ERG which is flat. and eventually she becomes blind, A tumor mass in the pelvis is diagnosed as an undifferentiated reserve cell neoplasm of the cervix. The patient's serum From the Departments Llf OphthalmLlILlgy (TCK, RMB, JAR, MJI. DB), NeurolLlgy and NeurolLlgical Surgery (RMB), and Internal Medicine (OK). WashingtLln University SChLlLlI Llf Medicine, St. LLluis, MissLluri December 1984 is tested for antibody against normal retinal tissue by the immunofluorescent complement fixation test and is found to "fix complement in the presence of normal retinal tissue," This is interpreted as presumptive evidence of the presence of antibody against normal retinal tissue, We are seeing a patient who appears to have a similar retinal degeneration associated with carcinoma of the breast. Case Report In July 1979, a 43-year-old white woman was admitted for evaluation of a mass of the right breast. She stated that she began to have blurred vision and "floaters" about 3 months before admission, Several years prior to this admission she underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy for dysfunctional uterine bleeding, She was not taking medication of any kind and denied family history of visual disorders, Physical examination revealed a well-developed, well-nourished woman whose examination was normal except for a 3-cm diameter firm, movable mass of the right breast without regional edema of lymphadenopathy, There was no visceral organomegaly, Her best-corrected visual acuity was "hand motions" in the right eye and 20/100 in the left eye, She had occasional cells without flare in the anterior chamber with intraocular pressures of 33 mm Hg in the right eye and 44 mm Hg in the left eye, Ocular fundus examination revealed narrowed retinal arterioles in both eyes. Visual field examination by kinetic perimetry revealed bilateral dense central scotomas and marked peripheral constriction in the right eye, She was treated with topical 1So prednisolone acetate to both eyes four times a day, 5% homatropine hydrobromide to both eyes four times a day, and 0.5% timolol maleate to both eyes every 12 hours, Complete blood count, Westergren erythrocyte sedimentation rate, SMA 12, and urinalysis were 239 Para neoplastic Retinopathy TABLE I. Paraneoplastic Syndromes Condition Paraneoplastic encephalomyelitis with bulbar involvement" 5.12 Paraneoplastic subacute cerebellar degeneration with bulbar involvement" 5. 9-11 Opsoclonus·· 5.9-11 Uveomeningitic syndrome6 Multifocal leukoencephalopathy5" Myasthenia gravis,···5.l3-17 Hyperviscosity syndromes"" 18-'0 Nutritional amblyopia Wernicke's encephalopathy" Paraneoplastic retinopathy' 8 Associated Pathology Oat cell lung, breast, or uterine carcinoma Ovarian, bronchiaL or breast carcinoma Breast, lung, or uterine carcinoma Breast carcinoma Thymoma Waldenstrbm's macrog-lobulinemia Multiple myeloma Leukemia Paraneoplastic nutri-tional deficiency states Paraneoplastic nutritional deficiency states Lung, breast. uterine, or rena I carcinoma Clinical Finclings Ophthalmoplegia Nystagmus Ptosis Ophthalmoplegia Nystagmus Facial weakness Spontaneous, conjugate, constant. large-amplitude saccades in all directions of gaze Decreased visual acuity Mild anterior uveitis Macular edema Papillitis Visual field defects Ptosis Ophthalmoparesis Chorioretinopa thy Optic disc edema Visual field defects MOtility disturbances Pupillary miosis and nonreactivity Ptosis Decreased visual acuity Visual field defects Nyctalopia Absent electroretinographic response Histopathology Perivascular cuffing with lymphocytes, neuronal loss, and microglial proliferation in hippocampal formation, amygdala, cingulate gyrus, occipital cortex, brain stem Loss of Purkinje cells Demyelination of superior cerebellar peduncles Degeneration of bulbar motor nuclei Parenchymatous degeneration of cerebellum involving mainly the Purkinje cells, and to lesser extent, the granular cells and dentate nuclei Unknown Total degeneration of myelin sheaths with preservation of axis cylinders Collections of small round cells (presumably lymphocytes) among muscle fibers and small blood vessels, single muscle fibers. or groups of fibers in state of degeneration Coagulative necrosis of retina Microinfarcts and cytoid bodies of retinal nerve fiber layer Hemorrhages throughout retina Unknown in nutritional amblyopia Varying degrees of necrosis Prominent blood vessels Hemorrhage of parenchymal struc-tures of thalamus, hypothalamus, mammillary bodies, periaqueductal region of fourth ventricle. anterior lobe of cerebellum Total degeneration of photoreceptor cell layer Marked loss of nuclei from the outer nuclear layer Melanophages in retina Normal choriocapillaris normal. FTA also was negative. A mammogram of the right breast was suggestive of a carcinoma. Complete metastatic evaluation including brain scan, bone scan, CT of the brain and orbits, and cerebrospinal fluid examination were normal. Therefore. on the fourth day of hospitalization, the patient underwent an uneventful right modified radical mastectomy. Histopathologic evaluation of the tissue revealed infiltrating ductal adenocarcinoma with extension to the edge of the tissue, but without extension to any of the 13 resected lymph nodes (Fig. 1). Tissue was negative for estrogen or progesterone receptors. A course of local chest wall radiation followed. 240 On treatment her pressures fell to 18 mm Hg in the right eye and 15 mm Hg in the left eye, but the mild cell and flare persisted. Six weeks postoperatively, her vision had deteriorated to "hand motions without light projection" in both eyes. An electroretinogram was obtained and demonstrated no response under photopic or scotopic conditions. The patient was placed on 60 mg of oral prednisone per day. After 2 weeks, she noticed a subjective improvement in her vision. Testing at this time revealed "finger counting" vision and mild peripheral constriction with central scotomas on kinetic perimetry in both eyes. The cells and flare in the anterior chamber Journal of Clinical Neuro-ophthalmology Klingele et aI. - , ,- . , ( .- " , . ... " . ., .. .. " J .. r-' 'A .- f , .". .. " " .. Ff' ~. I· 0.. . ~' : , ~ .. t - .. I " •• 0 .' ,. ". I' I ~. . {;. .... • j- I•I I , I ., ,I'· t, J J • I~ " ......... '" - , . -. , • j , I , - ." • , ': " • 1'" .. • " Figure 1. Photomicrograph of iniiltrating ductal adenocarcinoma from resected right breast mass. (Original magnification x250.) had cleared. Over the next 4 weeks all medications were slowly withdrawn. Her vision remained stable. Three weeks later, examination revealed narrowed retinal arterioles and marked retinal pigmentary mottling bilaterally (Figs. 24). Her vision has remained stabilized at "finger counting" in both eyes to the present time. Discussion The mechanism of induction of many of the nonmetastatic remote effects of cancer on the nervous system are not known. Numerous hypotheses exist2 - 4 Since neoplasms can be induced by a variety of toxic agents, it is postulated that the inciting agents which produce cancer also affect the nervous system causing the degenerative process.l~ At least one confusing neurological disorder associated with malignancy appears to have an infectious etiology and this mechanism is proposed for other paraneoplastic syndromes23 Serum hyperviscosity can produce nonmetastatic remote effects of myeloma20 Pharmacologically active hormone-like substances are known to be produced by malignant cells in oat cell carcinoma and may affect the nervous system.' Similarly, tumor-secreted toxin or tumor-induced nutritional deficiency states may playa role in the pathogenesis of paraneoplastic syndromes. I. 3.~} More than one paraneoplastic syndrome may be present in the same patient and may lead to a confusing c~~,bination of neurologic symptoms and sIgns. I. I ... Relevant to our case, however, is the pathologic observation of changes similar to autoimmune disease in the brain stem of the patient with paraneoplastic bulbar encephalitis, although no autoantibodies were detectedl~ Complement fixing autoantibodies isolated from the serum of a patient suffering with sensory paraneoplastic neuropathy are reported.· ~~ Keltner et al.~ believe they demonstrated antibodies to normal retina by immunofluorescent complement fixation in their case. We believe this patient's syndrome of rapidly progressive retinopathy with severe visual loss, evidenced by narrowed arterioles, pigmentary changes and extinguished ERG, to be unique. Although hereditary retinal dystrophy or retinotoxic drug ingestion might cause retinal degeneration with diminished ERG, we believe that these entities are excluded. December 1984 241 Paraneoplastic Retinopathy (0) (oJ Figures 2a and 2b. Fundus photographs (<I = right eye; b = left eye). showing relatively normal appearance except for narrowed arterioles. 242 Journal of Clinical Neuro-ophthalrnology December 1984 Figures 3a and 3b. FJuorl'scein angiogram (<7 = right eve; /' = left eve), earlv phase, showing narrowl'd arterioles, slow perfusIOn, irregular veins, and patchv RPE atrophv. Klingele et al. 243 Para neoplastic Retinopathy lbl Figures 4a and 4b. Fluorl'scein angiogram (tl = right eye; I, = left eye), late phase, showing narw\\'ed artl'rioles, slo\\' pl'rfusion, irregular veins, and patchy RPE atrophy. 244 Journal of Clinical Neuro-ophthalmology We feel that our patient experienced retinal degeneration which represents a nonmetastatic remote effect of a breast malignancy, possibly immunologically mediated, and we choose to call this syndrome paraneoplastic retinopathy. References 1. Posner, J.B.: Neurological complications of systemic cancer. Med. Oill. North Am. 63(4): 783-800, 1979. 2. Brain, L., and Adams, RD.: Epilogue: A guide to the classification and investigation of neurological disorders associated with neoplasms. In The Remote Effects of Callcer 011 the Nervous System,L. Brain and F.H. Norris, Jr., Eds. Grune & Stratton, New York. 1965, pp. 216-221. 3. Hildebrand, J.: II. Neurological paraneoplasia. In Perspectives ill Callcer Research. Paralleoplastic Sy", tromes, H.J. Tagnon and J. Hildebrand, Eds. Eur. J. Callcer Clill. Ollcol. 7: 969-990, 1981. 4. Posner, J.B.: Neurologic Complicatiolls of Systemic Callcer. Year Book Medical Publishers, Chicago, 1978, pp. 7-60. 5. Gilroy, J., and Meyer, J.5.: Medical Neurology (3rd ed.). Macmillan Publishing Co., Inc., New York, 1979, pp. 269-272. 6, Rudge, P.: Optic neuritis as a complication of carcinoma of the breast. Proc. Roy. Soc. Med. 66: 11061107,1973. 7. Sawyer, RA., Selhorst, J.B., Zimmerman, L.E., and Hoyt, W.F.: Blindness caused by photoreceptor degeneration as a remote effect of cancer. Am. J. Ophthalmol. 81: 606-613, 1976. 8. Keltner, J.L., Roth, A.M., and Chang, S.: Photoreceptor degeneration-A possible autoimmune disease. Arch Ophthalmol. 101: 564-569, 1983. 9. Ellenberger, C, Jr., and Netsky, M.G.: Anatomic basis and diagnostic value of opsoclonus. Arch. Ophthalmol. 83: 307-310,1970. 10. Ellenberger, C, Jr., Campa, J.F., and Netsky, M.G.: Opsoclonus and parenchymatous degeneration of the cerebellum. The cerebellar origin of an abnormal ocular movement. Neurology 18: 1041-1046, 1968. 11. Ross, AT, and Zeman, W.: Opsoclonus, occult carcinoma, and chemical pathology in dentate nuclei. Arch. Neurol. 17: 546-551, 1967. 12. Halperin, J-J., Richardson, E.P., Jr., Ellis, J., Ross, J.5., and Wray, S.H.: Para neoplastic encephalomyelitis and neuropathy. Report of a case. Arch. Neurol. 38: 773-775, 1981. 13. Rowland, L.P., Lisak, RP., Schotland, D.L., DeJesus, P.V., and Berg, P.: Myasthenic myopathy and thymoma. Neurology 23: 282-288, 1973. December 1984 Klingele et a!. 14. Sabiston, D.C: Diseases of the pleura, mediastinum and diaphragm. In HarriSOIl's Prillciples of llltemal Medicille, G. W. Thorn, R.D. Adams, E. Braunwald, K.V. Isselbacher, and RG. Petersdorf, Eds. McGraw-Hill Book Co., 1977, p. 1397. 15. Adams, RD.: Myasthenia gravis and episodic muscular weakness. In Harrisoll's Prillciples of Illtemal Medicille (8th ed.), G.W. Thorn, RD. Adams, E. Braunwald, K.V. Isselbacher, and R.G. Petersdorf, Eds. McGraw-Hill Book Co., New York, 1977, p. 1999. 16. Perlo, V.P., Schwab, R.5., and Castleman, B.:' Myasthenia gravis and thymoma. In The Remote Effects of Callcer 011 the Nervous System, L. Brain, and F.H. Norris, Jr., Eds. Grune & Stratton, New York, 1965, pp. 55-66. 17. Rowland, L.P., and Schotland, D.L.: Neoplasms and muscle disease. In The Remote Effects of Callcer 011 tile Nervous Slfstem, L. Brain and F.H. Norris, Jr., Eds. Grune & Stratton, New York, 1965, pp. 83-97 18. Solomon, A.: Neurological manifestations of macroglobulinemia. In The Remote Effects of CallCer 011 the NenJous System, L. Brain and F.H. Norris, Jr., Eds. Grune &'Stratton, New York, 1965, pp. 112124. 19. Ackerman, A.L.: Retinal problems in systemic disease. In Clillical Ophthalmology, Rel'ised EditiOlI1982, Vol. 5, T.D, Duane and E.A. Jaeger, Eds. Harper & Row, Philadelphia, 1982, sect. 42, pp. 4-5 20. Cunningham, R.D.: Retinopathy of blood dyscrasias. In Clillical Ophthalmology, Rel'ised Editioll1982, Vol. 3, T.D. Duane and E.A. Jaeger, Eds. Harper & Row, Philadelphia, 1982; sect. 18, pp. 1-8. 21. Victor, M.: The effects of nutritional deficiency on the nervous system. A comparison with the effects of carcinoma. In The Remote Effects of ClIlcer 011 the Nerl'ous System, L. Brain and F.H. Norris, Jr., Eds. Grune & Stratton, New York, 1965, pp. 134-161. 22. Gilmore, RL.: Recognizing the remote effects of malignancy on the nervous system. Geriatrics March: 102-111, 1979. 23. Richardson, E.P., Jr.: Progressive multifocal leukoencephalopathy. In Tile Remote Effects of Callcer all tile Nervous System, L. Brain and F.H. Norris Jr., Eds. Grune & Stratton, New York, 1965, pp. 6-16. Acknowledgment This work was supported in part by a grant from Research to Prevent Blindness, Inc., New York, New York (Department of Ophthalmology). Write for reprillts to: Terence G. Klingele, M.D., 16420 East Pavilion, Barnes Hospital Plaza, St. Louis, Missouri 63110. 245 |
