Journal of Neuro-Ophthalmology, September 1992, Volume 12, Issue 3

Optic neuropathy: a rare paraneoplastic syndrome.

A 63-year-old man developed gradually progressive bilateral loss of vision, cerebellar ataxia, and downbeat nystagmus. Visual acuity was 20/400 OD and 20/200 OS, with cecocentral scotomas OU. Fundus examination showed bilateral optic atrophy and a vitreous cellular reaction. MRI 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. Paraneoplastic optic neuropathy should be considered in patients with unexplained visual loss and malignancy, and our observations suggest a possible immunologic basis for this condition.

! 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. 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