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Show ! ouma! of Cl; II;,' a! Neun>' 0l'hthaill/ o! ogy 12( 3': 137- 141. 1992. Optic Neuropathy: A Rare Paraneoplastic Syndrome S. Malik, M. D., A. J. Furlan, M. D., P. J. Sweeney, M. D., G. S. Kosmorsky, D. O., and M. Wong, M. D. >(. 1992 Raven Press, Ltd., New York A 63- year- old man developed gradually progressive bilateral loss of vision, cerebellar ataxia, and downbeat nystagmus. Visual acuity was 20/ 400 aD and 20/ 200 as, with cecocentral scotomas au. Fundus examination showed bilateral optic atrophy and a vitreous cellular reaction. MRl of the brain was normaL CSF protein was elevated, with increased IgG levels but no malignant cells. Biopsy of a pulmonary lymph node showed undifferentiated small cell carcinoma. Neoplastic cells were positive for neuron- specific enolase. Serum contained IgG, which reacted with neuronal and glial cytoplasm and processes. IgG reactivity with systemic tissues and the patient's tumor was not different from that observed with control sera. Para neoplastic optic neuropathy should be considered in patients with unexplained visualloss and malignancy, and our observations suggest a possible immunologic basis for this condition. Key Words: Malignancy- Visualloss- Anti- central nervous system antibodies- Immunologic basis. From the Departments of Neurology ( S. M., A. j. F., P. j. S., G. S. K., M. W.) and Ophthalmology ( G. S. K.), Cleveland Clinic Foundation, Cleveland, Ohio, U. S. A. Address correspondence and reprint requests to Dr. Sudhir Malik, Department of Neurology, Cleveland Clinic Foundation, Cleveland, OH 44132, U. s. A. 137 The paraneoplastic syndromes ( PNS) comprise a group of diverse conditions that are manifest as the " remote effect" of certain cancers on the nervous system. They have been recognized for at least 25 years ( 1-- 4) and represent the nonmetastatic effect of a remote neoplasm ( 5). These disorders are rare and occur in less than 1% of unselected patients with cancer. Optic neuropathy is a particularly rare PNS reported in patients with mixed cell bronchial carcinoma ( 6), anaplastic oat cell carcinoma of the lung ( 7- 10), Hodgkin's disease ( 11), and lymphoma ( 1214). We report a patient with an initially unexplained, bilateral optic neuropathy and a small cell bronchogenic carcinoma in whom anti- central nervous system antibodies were subsequently demonstrated. CASE HISTORY A 63- year- old man with a 40- pack per year history of smoking presented with a 2- month history of gradually progressive bilateral loss of vision. Initially involving the left eye, he described it as a shade across the inferior half of the left visual field, slowly progressing over 3 weeks. This was followed, a month later, by sudden onset, blurring of vision in the right eye. Visual acuity continued to deteriorate over the next month and then stabilized bilaterally. Five months later, he noticed a persistent shimmering of vision bilaterally. This was followed by the subacute development of progressive gait ataxia, clumsiness of the hands, and intention tremor in both arms. There was no history of retinal degenerative disease or exposure to toxins. Past medical history included hypertension, gout, and left internal carotid endarterectomy for high- grade stenosis. The general physical examination was signifi- 138 S. MALIK ET AL. cant only for a harsh, grade 3/ 4 systolic murmur over the right upper sternal border, consistent with aortic stenosis. Neurologic examination revealed his mental status to be normal. There were no cranial, ocular, or carotid bruits. Both temporal arteries were soft, pulsating, and nontender. On neuro- ophthalmologic examination, he had a distance visual acuity of 20/ 200 au and 20/ 400 00 and J16 as at near. The pupillary examination revealed light near dissociation presumed to be secondary to poor visual acuity due to his optic neuropathy. He had coarse, downbeat nystagmus, which increased on lateral gaze. Funduscopic examination revealed moderate arteriolar narrowing and marked A- V nicking. There was bilateral optic disk pallor, with a mild vitreous reaction in the right eye. The extraocular movements were normal. Goldmann perimetry showed bilateral cecocentral scotomas and generalized constriction of the visual fields ( Fig. 1). No altitudinal defects were noted, despite his complaint of a shade in the inferior visual field. The remainder of the cranial nerve examination was normal. Muscle tone, strength, and sensory examinations were normal. Reflexes were hypoactive and symmetrical, with bilateral flexor plantar responses. Truncal titubation with asymmetric appendicular ataxia, left greater than right, was present along with an intention tremor and impaired rapid alternating movements. His gait was broad- based and ataxic with an inability to tandem walk. The Romberg test was positive. Follow- up over 3 months revealed the presence of vitreous cells bilaterally with an enlarging blind spot and central scotoma in the right eye, and a cecocentral scotoma in the left eye. There was a further deterioration of gait and a weight loss of 9 kg. Results of the laboratory investigation, including complete blood cell count with differential, blood chemistry, serum vitamin B12, thyroid function tests, serologic tests for syphilis, and a chest x- ray were unremarkable. Westergren sedimentation rate, rheumatoid factor, antinuclear antigen profile, and cryoglobulins, as well as serum and urine electrophoresis, were within normal limits. Angiotensin- converting enzyme and f32- microglobulin were also normal. An echocardiogram revealed moderate to severe aortic stenosis with aortic regurgitation. Carotid ultrasound and magnetic resonance imaging ( MRI) of the brain were normal. Cerebrospinal fluid ( CSF) analysis revealed a normal pressure of 16 cm of water, 2 RBClmm3 and 15 WBClmm 3 , of which 89% were lymphocytes and 9% were monocytes. The protein level was in- " 1,/ 1,01",,, 1, Vol. 12, No, 3, 1992 creased to 72 mg/ dl, and the glucose level was normal at 61 mg/ dl, with a blood glucose level of 99 mg/ dl. Cerebrospinal fluid IgG was increased to 18.7 mg/ dl ( n = 0.6-- 4.4 mg/ dl), as were the IgG synthesis rate and IgG/ albumin ratio to 57.29 mg/ day ( n = 0- 3.1 mg/ day) and 0.39 ( n = 0.07- 0.19), respectively. Oligoclonal bands were absent. Three separate samplings were negative for malignant cells or microorganisms. Pattern- reversal visual evoked responses demonstrated a delay in conduction along both visual pathways. The patient refused to have an electroretinogram. A bone scan, bone marrow biopsy, and an upper gastrointestinal endoscopy were all normal. A gallium scan, however, revealed intense focal activity over the right perihilar region and computed tomography of the chest showed extensive adenopathy in the retrocaval and azygos regions. Biopsy of the mass revealed a metastatic undifferentiated small cell carcinoma of the lung. The neoplastic cells were strongly positive for neuron- specific enolase and negative for common leukocyte antigen. The serum contained an IgG which bound diffusely to neuronal and glial cytoplasm and processes of normal human cortex, cerebellum, and optic nerve, and antibody reactivity occurred to an endpoint dilution of 1: 800. The IgG reactivity against other systemic tissues did not differ from control sera. Cerebrospinal fluid was not examined for similar antibody reactivity due to the patient's refusal of another lumbar puncture. A diagnosis of small cell carcinoma of the lung with paraneoplastic optic neuropathy and subacute cerebellar degeneration was made. Direct invasion of the optic nerves by neoplastic cells, though unlikely, could not be definitely excluded. Radiation therapy to the mediastinum, followed by systemic chemotherapy was instituted, with remission of the tumor. Upon follow- up at 6 months, no fall in antibody titer was observed, and the neurological and ophthalmologic status remained unchanged. The patient was admitted to another hospital 14 months later ( 24 months after the onset of illness), due to a recurrence of his tumor, and died. Unfortunately, the family refused permission for an autopsy. DISCUSSION Optic neuropathy is one of the rarest forms of paraneoplastic syndromes and has been described in only a few case reports ( 6- 14). It is not commonly considered in the differential diagnosis of visual loss, as symptoms may precede the devel- OPTIC NEUROPATHY 139 ._ ...... 1 AO. D. - Red o 0.5. - Black A B 0 ••", •.• ~..",. -;.-:' '~' .'-~ . -, =-- j" .. ~ ", ,/ I I '. -- 6ii: ';, /..'/\'~ .. / \ ~ .: \ ' ij1j j- ,~/ _ - ~ \, ~ rJr.\ • ". 1 . --"\ . , ','.... '.- :;;".../, \ " .,' i \, - '~\ ~ . 150 , _ 18I. l~" I' to~•• rr: j' ."" IV' , .. :..!..-" 4_ " 0 "..... ~.~::, : i~~; j "" 0' ' C.,--~~,- ~_','~_. J ~" " c.,. ' 0""""""". . _._ ~ 1\ l1''' lU. lon'' hlttln. CLEVELAND CLINIC FOUNDATION I I I CLEVELAND CLINIC FOUNDATION 00.0. - Red ~ 0.5. - Black ....... ~ l' I,., • FIG. 1. A and B: Goldmann visual fields showing the presence of bilateral cecocentrat scotomas. opment of symptoms from the primary neoplasm by many months. In most cases there is bilateral involvement, although it may begin unilaterally. The course is usually one of progressive visual deterioration over several days to weeks ( Cr8,1O), although loss of vision progressing over a few hours ( 14), or over a year have also been described ( 25), In some patients, partial or complete recovery of vision may occur, either spontaneously ( 8), or after treatment with steroids ( 10,13,14), The clinical picture initially suggested an anterior ischemic optic neuropathy ( AION). The patient complained of loss of vision in the left eye, describing it as a shade over the inferior half of the visual field. This type of visual field loss is characteristically seen in ischemic optic nerve disease. JClill Neuro- ophlhalmol, Vol. 12, No. 3, 1992 140 S. MALIK ET AL. However, the slow progression of symptoms over 3 weeks, and the absence of an inferior altitudinal defect on Goldmann perimetry are atypical for AION. Although an abrupt onset of visual symptoms, as described by the patient in the right eye, is more common in AION, loss of vision over hours may also be seen in paraneoplastic optic nerve disease ( 14). Furthermore, the presence of cells in the vitreous are not a feature of AION and pointed more toward an optic neuropathy of either inflammatory or infiltrative origin. An extensive evaluation for an infectious etiology, connective tissue disorders, vasculitis, and sarcoidosis was negative. The age of the patient and progressive deterioration in his neurological condition, associated with a normal magnetic resonance imaging of the brain and absence of oligoclonal bands in the cerebrospinal fluid, made multiple sclerosis an unlikely etiology. Although meningeal carcinomatosis is common in the setting of a cancer and is often difficult to diagnose in the early stages, the absence of headache, meningeal signs, and multiple cranial nerve palsies ( 15) suggested a different disorder. The CSF analysis, in addition, on three separate samplings, revealed normal glucose levels and no tumor cells. The development of a progressive optic neuropathy and prominent cerebellar dysfunction with nystagmus, intention tremor, and ataxia, associated with a small cell carcinoma of the lung in our patient was most consistent with a paraneoplastic syndrome. Subacute cerebellar degeneration is one of the best clinically and pathologically defined paraneoplastic syndromes, and is most often seen with neoplasms of the lung, ovaries, or breast ( 5). It frequently precedes detection of the tumor and may occur alone or as a part of a wider encephalomyelitis. It is characterized by the progressive development of truncal and appendicular ataxia, nystagmus, and occasionally vertigo. The pathogenesis of paraneoplastic optic neuropathy is unknown. Various etiologies have been suggested, including ( a) microscopic infiltration of the optic nerve by tumor cells ( 16), ( b) an inflammatory response ( 6), ( c) elaboration of a humoral toxin ( 8,15), or ( d) impairment of axonal flow ( 17). Yet another explanation may be the production of autoantibodies against the optic nerve. Antiretinal ganglion cell antibodies ( 18,19) and antibodies against retinal photoreceptor cells- the cancerassociated retinopathy ( CAR) syndrome ( 20-- 22), have been identified in patients with small cell carcinoma of the lung. Subsequently, Thirkill et al. ( 23) have demonstrated antibody titers of 1: 200 by Western Blot analysis against bovine optic nerve antigens in a patient with small cell carcinoma of the lung, the cancer- associated retinopath~ ( CAR) syndrome, and bilateral visual loss. Expenmental exposure of guinea pigs to the patient's serum lead to extensive demyelination of the optic nerves, suggesting that the loss of vision occurred through the disruption of optic nerve function ( 23). A unique feature of the present case is the demonstration of an antibody reaction directed against glial processes as well as neuronal and astrocytic components of normal human cortex, cerebellum, and optic nerve. Demonstration of this antibody suggests a possible immunologic basis for the optic neuropathy as a paraneoplastic syndrome. The antibody may have been produced as an autoimmune response against tumor antigens that are shared by normal neuronal and astrocytic antigens, or by the destruction of neuronal and astrocytic cells containing these antigens. Evidence in support of the former hypothesis has been demonstrated in small cell carcinoma of the lung associated with retinal degeneration ( 19,24,25). The neoplastic cells in our patient were strongly positive for neuron- specific enolase, an isoenzyme specific to neurons and amine precursor uptake and decarboxylation ( APUD) cells including neuroendocrine cells of the lung ( 26,27). It is also found in astrocytes as well as in oat cell carcinoma of the lung ( 28). This protein has been postulated to have an antigenic role in paraneoplastic retinal degeneration associated with oat cell carcinoma of the lung, and may elicit the formation of autoantibodies ( 18). It is possible that the IgG in the serum of our patient was reactive against neuron- specific enolase. This would explain the diffuse immunoreactivity exhibited against neuronal and astrocytic components of cortex, cerebellum, and optic nerve. The etiologic significance of the antibody demonstrated in our patient is still uncertain. It may have a role in the development of the visual loss, or may simply be present in the patient's serum as an epiphenomenon. 1£ a causal relationship can be established, detection of this antibody in patients with unexplained visual loss may be helpful in the early diagnosis of paraneoplastic optic neuropathy and small cell carcinoma of the lung. Subsequent efforts directed at prevention or treatment by immunomodulation may lead to a better systemic and neurologic prognosis. . Acknowledgment: We wish to thank Dr. Kurt Jaeckle In whose laboratory the Immunologic testing was done. OPTIC NEUROPATHY 141 REFERENCES 1. Brain WR, Norris FH, eds. The Yl'lIwte effl'cls of callC!' T OIl the Ill'n'OIiS Sl/ st",, 1. New York: Grune and Stratton, 1965. 2. Croft PB; Wilkinsun M. Carcinumatuus neuromyopathy: its incidence in patients with carcinoma of the lung and carcinoma of the breast. Lallcd 1963; 1: 184- 8. 3. Lambert E, Roorke ED. Myasthenic statl' and lung cancer. In: Brain WR, Norris F, eds. The relllote etfects or C, IIKcr OIl the lIen'OIiS Sl/ Stl'lll. New York: Grune and Stratton, 1965: 67- 80. 4. Norris F.' The remotl' effects of cancer on the Ol'rvous system. / Nellrol 1972; 201: 201- 10. 5. Anderson NE, Cunningham jM, Posner jB. Aut( limmune pathogenesis of p. uaneoplastic neurological syndromes. Crit ReI' Nl'IIYl'/ Jiol 191'\ 7; 3: 245- 99. 6. Pillay N, Gilbert Jj, Ebers GC, Brown jD. Internuclear ophthalmoplegia and " optic neuritis": paraneoplastic effects of bronchial carcinoma. Nl'IIroioSY 1984; 34: 788-- 91. 7. Davies POB. Carcinomatous neuropathy with papilloedema. Proc R Soc Med 1961; 54: 236. 8. Boghen 0, Sebag M, Michaud j. Paraneoplastic optic neuritis and encephalomyelitis: report of a case. Arch Nl'lIrol 1988; 45: 353- 6. 9. Walsh FB, Hoyt WF. Clillicaillellro- opht/ rallllology. Vol 3, 4th I'd. Baltimore: Williams & Wilkins, 1988: 1738-- 9 10. Waterston jA, Gilligan B5. Paraneoplastic optic neuritis and external ophthalmoplegia. Allst NZ I M,' d 1986; 16: 703- 4. 11. Hutchinson EC, Leonard Bj, Maudsley C, Yates PO. Neurological complications of the reticuloses. Braill 1958; 81: 7592 12. Richter RB, Moore RY. Non- invasive central nervous system disease associated with lymphoid tumors. loll// s Hopkins Med / 1968; 122: 271- 83. 13. Krauss AM, O'Rourke j. Lymphomatous optic neuritis. Arch Ophthalllwll963; 70: 17J- 5. 14. Coppeto jR, Monteiro MLR, Cannarozzi DB. Optic neuropathy associated with chronic lymphomatous meningitis. / Clill Nel/ ro- ophthallllol 1988; 8( 1): 39-- 43. 15. Fischer- Williams M, Bosanquet FD, Daniel PM. Carcinomatosis of the meninges: a report of three cases. Braill 1955; 78: 42- 58. 16. Susac 10, Smith IL, Powell 10. Carcinomatous optic neuropathy. Alii / Ophthallllol 1973; 76: 672- 9. 17. Appen RE, De Venecia G, Selliken IH, Giles LT. Meningeal carcinomatosis with blindness. Am / api/ thall/ wi 1978; 86: 661- 5. 18. Kornguth SE, Klein R, Appen R, Choate j. Occurrence of anti- retinal ganglion cell antibodies in patients with small cell carcinoma of the lung. Cancer 1982; 50: 1289- 93. 19. Liebermann F, Stefansson K, Marton LS, Atweh S. Antiretinal antibodies in serum of a patient with retinal degeneration on the background of an oat cell cancer of the lung. Neurology 1984; 34( suppl 1): 186. 20. Buchanan TAS, Gardiner TA, Archer DB. An ultrastructural study of retinal photureceptor degeneration associated with bronchial carcinoma. Am J Opht/ l< Ilmol 1984; 97: 277- 84 21. Keltner jL. Roth AM, Chang RS. Photoreceptor degeneration: possible autoimmune disorder. Arch Opllthalmol1983; 101: 564- 9. 22. Thirkill CE, Roth AM, Keltner jL. Cancer associated retinopathy. Arch O" hthalmol 1987: 372- 5. 23. Thirkill CE, Fitzgerald P, Sergot RC, et al. Cancer- associated retinopathy ( CAR syndrome) with antibodies reacting with retinal, optic- nerve and cancer cells. N Engl J Ml'd 1989; 321( 23): 1589- 94. 24. Grunwald GB, Klien R, Simmonds MA, Kornguth SE. Autoimmune basis for visual paraneoplastic syndrome in patients with small cell lung carcinoma. LlIIlCet 1985; 1: 65~ 1. 25. Kornguth SE, Kalinke T, Grunwald GB, Schutta H, Dalh D. Anti- neurofilament antibodies in the sera of patients with small cell carcinoma of the lung and with visual paraneoplastic syndrome. c. lIrccr Res 1986; 46: 2588-- 95. 26. Cole GA, Polak 1M, Wharton j, Marangos P, Pearse AGE. Neuron specific enolase as a useful histochemical marker for the neuroendocrine system in the lung. J Pat/ wi 1980; 132: 351- 2 ' 27. Tapia Fj, Polak 1M, Barbosa AjA, et al. Neuron specific enolase is produced by neuroendocrine tumors. Lancet 1981; 1: 808-- 11. 28. Vinores SA, Rubinstein LI. Simultaneous expression of G. F. A. protein and NSE by astrocytes. Neuyopatlwi Appl Nl'lIrobiol 1985; 11: 349- 59. I ( Ii" Nellro- ophthalmol, Vol 12. No. 3, 1992 |