Paraneoplastic Optic Neuropathy Associated With Purkinje Cell Antibody-2 in a Patient With Small Cell Lung Cancer

Although still rarely diagnosed, amyloid light chain (AL) amyloidosis is the most common form of systemic amyloidosis. It is characterized by misfolded monoclonal immunoglobulin light chain fragments that accumulate extracellularly as amyloid fibrils, with consequent organ dysfunction. We report 2 such cases where initial symptoms and signs were identical to and mistaken for those of giant cell arteritis, associated with polymyalgia rheumatica. Neither patient responded to high-dose corticosteroids; instead, their temporal artery biopsies revealed amyloid deposits and other investigations confirmed a diagnosis of systemic AL amyloidosis. Review of the literature reveals similar cases of diagnostic confusion spanning 75 years. We have summarized the findings and learning points from cases reported in the past 30 years and highlight the need for increased awareness and investigation of this underrecognized syndrome.

Clinical Observation Paraneoplastic Optic Neuropathy Associated With Purkinje Cell Antibody-2 in a Patient With Small Cell Lung Cancer Jonathan A. Micieli, MD, CM, Edward A. Margolin, MD Abstract: Paraneoplastic optic neuropathy (PON) is a rare cause of vision loss usually associated with small cell lung cancer. Patients with this condition usually test positive for anti-collapsin response mediating protein-5 (CRMP-5). We describe a case of a 57-year-old woman with bilateral vision loss with the characteristic features of CRMP-5 PON including bilateral optic disc edema and vitreous cells. However, she was negative for anti-CRMP-5 including a negative Western blot on two occasions, but positive for Purkinje Cell Antibody (PCA)-2. Although paraneoplastic antibodies are more predictive of an underlying cancer than a specific syndrome, previously PON has not been associated with PCA-2. Based on this observation, we recommend that the workup should include PCA-2 antibodies in patients who present with bilateral optic neuropathy and vitreous cells. Journal of Neuro-Ophthalmology 2017;37:53-55 doi: 10.1097/WNO.0000000000000458 © 2016 by North American Neuro-Ophthalmology Society P araneoplastic optic neuropathy (PON) is a rare cause of vision loss that may occur in association with small cell lung cancer or other neoplasms (1). Most patients with PON test positive for anti-collapsin response mediating protein-5 (CRMP-5), the antibody that defines this syndrome (2-4). In the largest cohort of patients reported with this condition, 9 of 15 patients had vitreous cells in addition to subacute vision loss, visual field defects, and optic disc edema (2). Although vision loss has been reported as the only symptom (4), PON almost always coexists in the setting of multifocal neurological dysfunction, Department of Ophthalmology and Vision Science, University of Toronto, Toronto, Ontario, Canada. The authors report no conflicts of interest. Address correspondence to Edward A. Margolin, MD, Department of Ophthalmology and Vision Science, University of Toronto, 801 Eglington Avenue W, Suite 301, Toronto, ON, M5N 1E3; E-mail: [e-mail] Micieli and Margolin: J Neuro-Ophthalmol 2017; 37: 53-55 most commonly peripheral neuropathy, autonomic neuropathy, and cerebellar ataxia (5). We report a patient with optic neuropathy, vitritis, and peripheral neuropathy manifesting as a paraneoplastic syndrome resembling that associated with anti-CRMP-5 antibodies. However, this patient was negative for CRMP-5 and positive for a distinct autoantibody, Purkinje Cell Antibody (PCA)-2. CASE REPORT A 57-year-old woman was evaluated in an emergency department with a 2-week history of bilateral vision loss. She also reported painful sensations in both her feet that started at the same time. Her medical history was significant for coronary artery disease, depression, and chronic obstructive pulmonary disease with a 40-pack year smoking history. Her medications were acetylsalicylic acid, rosuvastatin, bisoprolol, duloxetine, tiotropium bromide, and budesonide/formoterol inhalers. After examination by an ophthalmologist revealed a visual acuity of 20/25 in each eye, bilateral optic disc edema and large vitreous cells (Fig. 1), the patient was admitted to hospital for further evaluation. Magnetic resonance imaging (MRI) of the brain revealed scattered periventricular, deep white matter changes on FLAIR sequences. Owing to a suspicion of demyelinating disease, she underwent an MRI of the spine, which revealed no abnormalities of the spinal cord, but incidentally detected a large middle mediastinal mass with right hilar adenopathy. Biopsy of the mediastinal mass showed small cell lung carcinoma. The patient underwent 4 rounds of chemotherapy with cisplatin and etoposide, 15 sessions of radiotherapy, and 10 sessions of prophylactic radiotherapy to the brain. To further clarify the etiology of her vision loss, the patient was referred to our neuro-ophthalmology service 4 months after the onset of visual symptoms. Visual acuity was 20/25 in each eye, and there was no relative afferent 53 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation FIG. 1. There is bilateral optic disc edema and vitritis. Large anterior vitreous cells were appreciated on slit-lamp examination. pupillary defect. Ophthalmoscopy revealed superior optic disc pallor with corresponding inferior visual field defects in each eye (Fig. 2). Neurologic examination demonstrated decreased vibration sense, pinprick, and temperature distally in both legs. A clinical diagnosis of PON and peripheral neuropathy was made and a paraneoplastic panel revealed elevated PCA-2 titers (1:61,440) but negative titers and Western blot for anti-CRMP-5 (this was repeated twice). The patient's vision and neuropathy remained stable 8 months later and her cancer remained clinically and radiologically stable. DISCUSSION PCA-2 was the seventh IgG found to be directed against cytoplasmic or nuclear onconeural antigens and unambiguously FIG. 2. Automated visual fields (Humphrey 24-2) reveal bilateral inferior defects corresponding to superior optic disc pallor found on examination. 54 Micieli and Margolin: J Neuro-Ophthalmol 2017; 37: 53-55 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Observation identifiable in patients with a paraneoplastic syndrome. In the original report by Vernino and Lennon (6) identifying PCA-2, 9 patients presented with mixed neurological syndromes of which 8 had confirmed small cell lung cancer. The most commonly reported neurological signs were limbic encephalitis in 3 patients, cerebellar ataxia in 3, and brainstem encephalitis in 2. Like other antibodies associated with small cell lung cancer, PCA-2 is not specific for a single neurological syndrome, but is highly associated with a certain type of cancer (6,7). However, there have been no previous reports of PON associated with this autoantibody. Similar to PCA-2, CRMP-5 is highly associated with small cell lung cancer because it may be aberrantly expressed by this neoplasm (5). In a review of approximately 60,000 patients, seropositivity for CRMP-5 or PCA-2 was found in 47% and 53%, respectively, of patients with small cell lung cancer (7). In the same study, CRMP-5 IgG was found to frequently accompany PCA-2 (44% of patients with PCA-2 were positive for CRMP-5). One potential explanation for the absence of CRMP-5 in our patient is that after treatment, CRMP-5 may have been suppressed. Previous cases have demonstrated a dramatic decrease in CRMP-5 levels after treatment with carboplatin and etoposide (4). However, CRMP-5 titers were undetectable including a negative Western blot on 2 occasions in our patient. To our knowledge, there has been no reported case where CRMP-5 has been suppressed to undetectable levels after treatment of small cell lung cancer. Patients suspected of having a paraneoplastic disorder should undergo investigations for antineuronal antibodies in their serum and cerebrospinal fluid. The presence of these antibodies then directs the search toward cancers of specific organs associated with a particular antibody (8). Typically, these patients have a low tumor burden and the underlying cancer may be hard to find. Based on this report, we recommend that the workup should include Micieli and Margolin: J Neuro-Ophthalmol 2017; 37: 53-55 PCA-2 antibodies in patients who present with bilateral optic neuropathy and vitreous cells. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: J. A. Micieli and E. A. Margolin; b. Acquisition of data: J. A. Micieli and E. A. Margolin; c. Analysis and interpretation of data: J. A. Micieli and E. A. Margolin; Category 2: a. Drafting the manuscript: J. A. Micieli and E. A. Margolin; b. Revising it for intellectual content: J. A. Micieli and E. A. Margolin; Category 3: a. Final approval of the completed manuscript: J. A. Micieli and E. A. Margolin. REFERENCES 1. Rahimy E, Sarraf D. Paraneoplastic and non-paraneoplastic retinopathy and neuropathy: evaluation and management. Surv Ophthalmol. 2013;58:430-458. 2. Cross SA, Salomao DR, Parisi JE, Kryzer TJ, Bradley EA, Mines JA, Lam BL, Lennon VA. Paraneoplastic autoimmune optic neuritis with retinitis defined by CRMP-5-IgG. Ann Neurol. 2003;54:38-50. 3. Sheorajpanday R, Slabbynck H, Van De Sompel W, Galdermans D, Neetens I, DeDeyn PP. Small cell lung carcinoma presenting as collapsin response-mediating protein (CRMP)-5 paraneoplastic optic neuropathy. J Neuroophthalmol. 2006;26:168-172. 4. Margolin E, Flint A, Trobe JD. High-titer collapsing responsemediating protein-associated (CRMP-5) paraneoplastic optic neuropathy and vitritis as the only clinical manifestations in a patient with small cell lung carcinoima. J Neuroophthalmol. 2008;28:17-22. 5. Yu Z, Kryzer TJ, Griesmann GE, Kim K, Benarroch EE, Lennon VA. CRMP-5 neuronal autoantibody: marker of lung cancer and thymoma-related autoimmunity. Ann Neurol. 2001;49:146-154. 6. Vernino S, Lennon VA. New purkinje cell antibody (PCA-2): marker of lung cancer-related neurological autoimmunity. Ann Neurol. 2000;47:297-305. 7. Pittock SJ, Kryzer AS, Lennon VA. Paranoeplastic antibodies coexist and predict cancer, not neurological syndrome. Ann Neurol. 2004;56:715-719. 8. Bataller L, Dalmau JO. Paraneoplastic disorders of the central nervous system: update on diagnostic criteria and treatment. Semin Neurol. 2004;24:461-467. 55 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.