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Show Journal of Neuro- Ophthalmology 21( 3): 164- 167, 2001. • 2001 Lippincott Williams & Wilkins, Inc., Philadelphia Original Contribution Paraneoplastic Optic Neuropathy and Cerebellar Ataxia With Small Cell Carcinoma of the Lung Madhav R. Thambisetty, MD, DPhil, Clemens R. Scherzer, MD, Zhiya Yu, MD, PhD, Vanda A. Lennon, MD, PhD, and Nancy J. Newman, MD Bilateral optic neuropathy and subacute cerebellar ataxia were manifestations of a paraneoplastic neurologic disorder in a woman found to have small cell carcinoma of the lung. Serologic tests revealed a neuronal autoantibody specific for CRMP- 5, a 62- kd member of the collapsin response- mediating protein family. Unexplained optic neuropathy in the setting of subacute cerebellar ataxia should cause suspicion of a paraneoplastic disorder and prompt testing for this autoantibody, especially in patients at risk for lung carcinoma. Key Words: Neuroimmunology- Oncology. - Neuro- ophthalmology- Paraneoplastic optic neuropathy is rare ( 1- 5) but recognized with small cell lung carcinoma. Accompanying autoantibodies of neuronal ( 3,4) and oligodendrocyte ( 5) specificities have been reported. We report a patient with bilateral optic neuropathy and subacute cerebellar ataxia who was found to have small cell lung carcinoma and a serum autoantibody specific for a recently defined 62- kd neuronal antigen named collapsin response- mediating protein- 5 ( CRMP- 5) ( 6). Manuscript received April 3, 2001; accepted June 25, 2001. Dr. Yu is a postdoctoral fellow of the Myasthenia Gravis Foundation of America. Dr. Newman is a Research to Prevent Blindness Lewis R. Wasserman Merit Award recipient. Supported in part by a departmental grant ( Ophthalmology) from Research to Prevent Blindness, Inc., New York, New York, and National Institutes of Health CORE Grant P30- EYO. Dr. Lennon received support from grant CA- 37343 from the National Cancer Institute and the Mayo Clinic Cancer Center. From the Departments of Neurology ( TRM, CRS, NJN), Ophthalmology ( NJN), and Neurosurgery ( NJN), Emory University School of Medicine, Atlanta, Georgia; and the Departments of Immunology, Neurology, and Laboratory Medicine/ Pathology ( ZY, VAL), Mayo Clinic and Mayo Foundation, Rochester, Minnesota. Address correspondence and reprint requests to Nancy J. Newman, MD, Neuro- Ophthalmology Unit, Emory Eye Center, 1365- B Clifton Road NE, Atlanta, GA 30322; e- mail: ophtnjn@ emory. edu. CASE REPORT A 72- year- old woman presented in May 1999 with bilateral reduction in visual acuity, progressive gait instability, and bilateral occipital headaches developing during the course of 2 weeks. Initial evaluation revealed bilaterally swollen optic nerves with best- corrected visual acuity of 20/ 60 OU. Neurologic examination results were normal except for gait instability. Computed tomography ( CT) of the brain and orbits, with and without contrast, was unremarkable. Magnetic resonance imaging could not be obtained because of a pacemaker implanted for sick- sinus syndrome. Her erythrocyte sedimentation rate was 46 mm/ h. Temporal artery biopsy results were normal, as were electromyography ( including repetitive motor nerve stimulation) and nerve conduction studies. An electroretinogram ( ERG) was not performed. Past medical history was notable for hypertension, bilateral carotid endarterectomies, depression, and total abdominal hysterectomy 20 years earlier for benign pathology. Medications included trazodone, fluoxetine, verapamil, and aspirin. She had smoked cigarettes ( 40- pack- year history). The patient's visual acuity declined during several months, and she developed appendicular ataxia. Ophthalmologic examination in September 1999 revealed visual acuity of 20/ 200 OU and persistent bilateral optic disc edema. Lumbar puncture revealed a cerebrospinal fluid ( CSF) opening pressure of 13 cm with 32 white blood cells ( 86% lymphocytes, 13% monocytes) and 130 mg/ dL of protein ( normal < 60 mg/ dL). Syphilis serology and Venereal Disease Research Laboratories studies of CSF were nonreactive. Viral, fungal, and acid- fast bacillus culture results of CSF and serum were negative. Skin test results for tuberculosis immunity were negative. Radionuclide bone scan and chest radiograph were unremarkable. 164 NEUROPATHY AND ATAXIA WITH SMALL CELL CARCINOMA OF THE LUNG 165 By December 1999, the patient's visual acuity had declined to 20/ 400 OU. She now had a left afferent pupillary defect, central scotomas in both visual fields, and bilateral disc edema without substantial arterial attenuation. She had hypophonia and dysphagia, requiring a gastrostomy tube for nutrition and was confined to bed by ataxia. Fine and rapidly alternating finger movements were impaired on the left, and she had mild dysmetria of the left arm and leg. A lung nodule found by chest CT scan in the right upper lobe was identified as small cell carcinoma by CT- guided biopsy. Two CSF specimens were negative for malignant cells by cytologic examination. Serologic testing results for the carcinoma- associated retinopathy antibody were negative. A paraneoplastic autoantibody panel revealed P/ Q- type calcium channel and CRMP- 5 antibodies consistent with autoimmunity related to small cell lung carcinoma. Immunoprecipitation assays revealed P/ Q- type calcium channel antibody ( 221 pmol/ L; normal < 20 pmol/ L). Immunofluorescence assays ( 7,8) ( at 1: 60 dilution) were negative for type 1 Purkinje cell cytoplasmic antibody ( PCA- 1, or anti- Yo), PCA- 2, PCA-Tr, ANNA- 1 ( or anti- Hu), ANNA- 2 ( or anti- Ri), and amphiphysin antibodies. However, an antineuronal IgG revealed that up to 1: 30,720 dilution had the pattern of CRMP- 5 autoantibody ( 6). In Western blots, the patient's IgG bound to a 62- kd brain protein coinciding with the CRMP- 5 band yielded by a positive control IgG, and to a recombinant human CRMP- 5 protein ( Gen- Bank # AF157634) but not to recombinant CRMP- 2 or CRMP- 3 proteins ( 6). In additional studies, ( Fig. 1) the patient's IgG bound to a 62- kd retinal protein, as did IgG in a CRMP- 5- positive control patient's serum ( and a CRMP- 5- specific monoclonal IgG ( 6) [ data not shown]). After three cycles of plasmapheresis and two cycles of cisplatin and etoposide, the patient refused further chemotherapy. She died 3 months later. FIG. 1. Proteins in aqueous extracts of rat brain and bovine retina, and a recombinant full- length human collapsin response-mediating protein- 5 ( CRMP- 5) protein ( GenBank # AF157634) were probed by Western blot with sera from a CRMP- 5- positive control patient, the patient of this report, and a healthy subject, all at 1: 200 dilution. The molecular weight of each native heavy band is 62 kd. DISCUSSION Autoimmune paraneoplastic disorders of the central nervous system are mediated by antitumor immune responses directed against antigens common to a specific tumor ( often occult) and the nervous system. The neurologic manifestations are varied and are not attributable to metastatic invasion of neural tissue by neoplastic cells. In the past decade, several IgGs specific for neuronal cytoplasmic and nuclear components have been defined as serologic markers of paraneoplastic neurologic autoimmunity. Those reflecting immune responses initiated by proteins in small cell lung carcinoma ( ANNA- 1, ANNA- 2, PCA- 2, amphiphysin, and CRMP- 5) ( 6- 8) are not found in healthy subjects, are lower in frequency and titer in patients with small cell lung carcinoma uncomplicated by a paraneoplastic neurologic disorder ( 9), and are more common with certain neurologic presentations than with others; however, no autoantibody is predictive of a discrete neurologic syndrome ( 8). Detection of one of these proteins suggests the autoimmune basis of the presenting neurologic disorder and focuses the search for a specific neoplasm. Our patient had the rare paraneoplastic entity of optic neuropathy in combination with cerebellar ataxia and dysphagia. Her P/ Q- type calcium channel antibody raises the possibility of unrecognized Lambert- Eaton syndrome, despite a negative EMG study. Another possibility includes the presence of P/ Q- type calcium channel antibodies in the absence of Lambert- Eaton syndrome. Table 1 compares the clinical features reported in cases of paraneoplastic optic neuropathy with small cell lung cancer. All patients presented with visual loss ( 1- 5). Disc edema was a presenting feature in all but one case ( 3). With one exception ( 2), there was concurrent cerebellar dysfunction. In all cases, lung carcinoma was found after the onset of visual symptoms. The first autoantibody related to paraneoplastic optic neuropathy was described by Malik et al. ( 3) as an IgG that bound to neuronal and glial cytoplasm but not to systemic tissues. Unlike CRMP- 5 IgG ( 6), it did not bind to the lung neoplasm. A second ( named anti- CV2) was reported by De la Sayette et al. ( 5) as an IgG that bound to a 66- kd brain protein, earlier reported to be an oligo-dendrocyte- restricted antigen. A third was described by Luiz et al. ( 4) as an IgG that bound to a 60- kd protein expressed in retina, optic nerve, cerebellum, and cerebral cortex. Unlike paraneoplastic optic neuropathy, several distinct autoantibodies have been described in cancer-associated retinopathy ( CAR) syndrome ( 10). In the original description of the CAR syndrome, Thirkill et al. ( 11) reported the presence of serum autoantibodies against specific protein components of both retina and optic nerve. Our patient's serum contained two autoantibody markers of encephalomyeloneuropathy related to small cell lung carcinoma. The P/ Q- type voltage- gated calcium channel antibody is most frequently found in patients with Lambert- Eaton myasthenic syndrome, but it is also J Neuro- Ophthalmol, Vol. 21, No. 3, 2001 166 MADHAVR. THAMBISETTY ET AL. TABLE 1. Comparison of clinical features of previously reported cases of paraneoplastic optic neuropathy with small cell carcinoma of the lung Author Age/ sex Vision loss Visual acuity Visual fields Fundus Pillay et al. ( 1) 1984 56/ M Gradually progresive, OU 20/ 100 OU Not reported Disc swelling OS Boghen et al. ( 2), 1988 63/ M Acute, OD 3/ 200 OD Central scotoma, inferior bundle defect OD Disc swelling OD Malik et al. ( 3), 1992 Luiz et al. ( 4), 1998 63/ M 59/ F Gradually progressive, OU Acute, OU 20/ 200 OU 20/ 30 OD 20/ 40 OS Cecocentral scotomas. generalized constriction OU Severe constriction OU Disc pallor, moderate arteriolar narrowing. marked AV nicking OU Disc edema OU de la Sayette et al. ( 5), 1998 62/ M Acute, OS 20/ 400 OS Central scotoma OS Disc edema OU Present report 72/ F Acute, OU 20/ 200 OU Cecocentral scotomas OU Disc edema OU * The diagnosis of " mixed bronchial carcinoma" is consistent with the common cellular origin of squamous cell, adenocarcinoma, and small cell carcinoma of the lung. AV, antrioventricular; CNS, central nervous system; EOM, extraocular movements; F, female; INO, internuclear ophthalmoplegia; M, male. encountered with cerebellar ataxia ( 8). The second autoantibody was CRMP- 5 specific by immunofluorescence and Western blot criteria ( 6). It bound to cytoplasm of central and peripheral nervous system neurons, to 62- kd proteins extracted from brain and retina ( as did a CRMP- 5- positive control serum), and to recombinant human CRMP- 5 ( Fig. 1) but not to recombinant CRMP- 2 or CRMP- 3 ( data not shown). The CRMP family of proteins is believed to mediate growth guidance cues during neurogenesis ( 12). CRMP- 2 has been found in embryonic mouse retina in the inner layer of the differentiating cells and growing axons of the ganglion cells ( 10). The oligodendrocyte-reactive anti- CV2 antibody was reported to be specific for CRMP- 3, but it did not to bind to a recombinant CRMP- 3 protein ( 13). On neurologic, oncologic, and Western blot grounds, Yu et al. ( 6) have proposed that the anti- CV2 autoantibody in all likelihood is CRMP- 5 specific. The exclusively oligodendrocyte binding attributed to anti- CV2 ( 5) may reflect a tissue fixation artifact ( 6). Our patient illustrates the diagnostic importance of appropriate autoimmune serologic testing when the differential diagnosis includes a paraneoplastic etiology. CRMP- 5 autoantibody is particularly pertinent in a patient presenting with unexplained optic neuropathy, especially with early disc edema, with or without other neurologic signs. Diagnostic investigations for small cell carcinoma should be performed, particularly in patients with known risk factors for lung cancer. REFERENCES 1. Pillay N, Gilbert JJ, Ebers GC, et al. Internuclear ophthalmoplegia and " optic neuritis": paraneoplastic effects of bronchial carcinoma. Neurology 1984; 34: 788- 91. 2. Boghen D, Sebag M, Michaud J. Paraneoplastic optic neuritis and encephalomyelitis: report of a case. Arch Neurol 1988; 45: 353- 6. 3. Malik S, Furlan AJ, Sweeney PJ, et al. Optic neuropathy: a rare paraneoplastic syndrome. J Clin Neuroophthalmol 1992; 12: 137- 41. 4. Luiz JE, Lee AG, Keltner JL, et al. Paraneoplastic optic neuropathy and autoantibody production in small- cell carcinoma of the lung. J Neuroophthalmol 1998; 18: 178- 81. 5. de la Sayette V, Bertran F, Honnorat J, et al. Paraneoplastic cerebellar syndrome and optic neuritis with anti- CV2 antibodies: clinical response to excision of the primary tumor. Arch Neurol 1998; 55: 405- 8. 6. 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Ann Neurol 2000; in press. / Neuro- Ophthalmol, Vol. 21, No. 3, 2001 NEUROPATHY AND ATAXIA WITH SMALL CELL CARCINOMA OF THE LUNG 167 EOM Associated findings Serology Treatment Clinical course Limitation of adduction OU Paralysis of upward gaze, mild limitation of horizontal gaze OU Normal Normal Normal Normal VI, VII, IX, X palsies, internuclear ophthalmoplegia, dysarthria, intention tremor, dementia Sensorimotor polyneuropathy, depression, irritability Downbeat nystagmus, gait ataxis, intention tremor, truncal titubation Gaze evoked, horizontal jerk nystagmus, dysarthria, axial dysmetria, truncal ataxia, gait instability Vertical nystagmus, dysarthria, gait instability, dysmetria of left arm and leg Gait instability, impaired fine finger and rapid alternating movements of left arm, dysmetria of both left arm and leg Not reported Not reported IgG binding to neuronal and glial cytoplasm in human cortex, cerebellum, optic nerve IgG binding to 60- kd protein in bovine optic nerve, retina, cerebellum, and cerebral cortex IgG (" anti- CV2") binding to oligodendrocytes in rat cerebellum, brainstem, spinal cord, and optic chiasm IgG binding to 62- kd protein in rat brain and bovine retina, and to recombinant human CRMP- 5. Pneumonectomy* Tumor radiation Mediastinal radiation, systemic chemotherapy 6 cycles cisplatin and etoposide chemotherapy, pulse IV methylprednisolone 1 g/ day for 5 days Tumor excision, cisplatin and etoposide chemotherapy, mediastinal and subclavicular radiation 2 cycles of cisplatin and etoposide chemotherapy, 3 cycles of plasmapheresis Resolution of disc swelling, worsening visual acuity, persistent INO, death after 9 months from sepsis, visceral ( but not CNS) metastases at autopsy Stable visual ocular motor status, worsening of encephalitis, death after 9 months Tumor remission at 6 months without change in neurologic and ophthalmologic status, death after 24 months from tumor recurrence Improved visual acuity and visual fields, improved dysmetria and gait at 9 months, no radiologic evidence of tumor recurrence or metastases at 13 months Improved speech and cerebellar symptoms, normal fundi without significant improvement in visual acuity at 1 month, no tumor recurrence at 2 years Stable neurologic and ophthalmologic status 1 week after chemotherapy, death after 3 months 8. 7. 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