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Show ORIGINAL CONTRIBUTION High- Titer Collapsin Response- Mediating Protein- Associated ( CRMP- 5) Paraneoplastic Optic Neuropathy and Vitritis as the Only Clinical Manifestations in a Patient With Small Cell Lung Carcinoma Edward Margolin, MD, Andrew Flint, MD, and Jonathan D. Trobe, MD Abstract: Paraneoplastic optic neuropathy ( PON) is a rare syndrome usually associated with small cell lung carcinoma. In the 27 rigorously reported cases, neurologic manifestations other than visual loss have been present in all but 2. In the single case in which vision improved in response to treatment of the cancer, the collapsin response- mediating protein ( CRMP)- 5 titer did not change, and the ophthalmic examination was not detailed. We describe a patient with optic neuropathy and vitritis as the only clinical manifestations of PON marked by an extremely high titer of CRMP- 5 antibody. Treatment of the underlying small cell lung cancer coincided with resolution of the visual abnormalities and a dramatic decrease in the CRMP- 5 titer. (/ Neuro- Ophthalmol 2008; 28: 17- 22) Paraneoplastic syndromes represent remote and secondary effects of cancers not related to metastatic spread or direct invasion ( 1). Paraneoplastic optic neuropathy ( PON) is a rare syndrome usually associated with small cell lung carcinoma ( 2). After the discovery in 2001 of collapsin response- mediating protein ( CRMP- 5), the antibody that defines this syndrome, 27 cases of PON have been rigorously described ( 2- 6). Neurologic manifestations other than visual loss were present in all but two of these cases ( 3,6). In one of these cases ( 3) the patient died despite treatment directed at the underlying cancer; in the other ( 6) vision improved in response to treatment of the cancer, but the CRMP- 5 titer did not change and the ophthalmic features were not detailed. Departments of Ophthalmology and Visual Sciences ( EM, JDT), Kellogg Eye Center, Neurology ( JDT), and Pathology ( AF), University of Michigan, Ann Arbor, Michigan. Address correspondence to Jonathan D. Trobe, MD, Kellogg Eye Center, 1000 Wall St., Ann Arbor, MI 48109; E- mail: jdtrobe@ umich. edu We describe a patient with optic neuropathy and vitritis as the only clinical manifestations of a paraneoplastic syndrome marked by an extremely high titer of CRMP- 5 antibody. Treatment of the underlying cancer coincided with resolution of the visual abnormalities and a dramatic decrease in the CRMP- 5 titer. CASE REPORT A 67- year- old woman had a 6- month history of slowly progressive visual loss in both eyes. She reported fatigue during the same period but no other symptoms. She had smoked a pack of cigarettes daily for the past 30 years. Best- corrected visual acuity was 20/ 70 in the right eye and finger counting in the left eye. There was no relative afferent pupillary defect. Ophthalmoscopy revealed moderate vitreous cells and optic disc swelling bilaterally ( Fig. 1). Humphrey visual fields revealed a mean deviation of 15 dB in the right eye and 15.8 dB in the left eye without localizable features ( Fig. 2). Results of the neurologic examination were otherwise normal. Results of MRI of the brain and orbits were normal. Lumbar puncture revealed a normal opening pressure and a normal cerebrospinal fluid ( CSF) formula except for a mildly elevated protein level of 56 mg/ dL. Serum and CSF angiotensin- converting enzyme ( ACE), Bartonella henselae, Toxoplasma gondii, Borrelia burgdorferi, herpes simplex virus ( HSV), herpes zoster virus ( HZV), syphilis, HLA- B27, HLA- A29, purified protein derivative ( PPD), Bartonella titers, and lysozyme levels were normal. Retinal fluorescein angiography revealed mild late optic disc leakage in both eyes ( Fig. 3). CT of the chest, abdomen, and pelvis disclosed lymph node enlargement involving the right hilum and subcarinal regions but no other abnormalities ( Fig. 4). Bronchoscopy with needle aspiration was nondiagnostic. A 3- day course of 1 g/ day intravenous methylprednisolone provided no improvement in vision, vitritis, or optic disc edema. J Neuro- Ophthalmol, Vol. 28, No. 1, 2008 17 J Neuro- Ophthalmol, Vol. 28, No. 1, 2008 Margolin et al FIG. 1 . Fundus photography performed at presentation shows bilateral optic disc swelling and vitreous haze. A paraneoplastic antibody panel disclosed a CRMP- 5 IgG titer of 1: 245,760, one of the highest ever reported by the Mayo Clinic Neuroimmunology Laboratory. Based on this finding, the patient underwent mediastinocopy, which produced frozen sections negative for neoplasm. On permanent section, one of eight lymph nodes demonstrated small cells with fine chromatin and scant cytoplasm. On immunohistochemical analysis, these cells stained strongly and uniformly for CD56 ( Fig. 5). The diagnosis of small cell lung carcinoma was finally made. Staging with positron emission tomography revealed increased uptake limited to the right hilar and subcarinal lymph nodes. Neurologic examination continued to reveal no abnormalities. Treatment with carboplatin and etoposide and concurrent radiotherapy was started. Five months after the initiation of treatment, a repeat CT of the chest demonstrated a decrease in the size of the hilar lymphadenopathy and complete resolution of subcarinal lymphadenopathy ( Fig. 6). At a follow- up neuro- ophthalmologic visit 6 months after the initial presentation, visual acuity was 20/ 20 in each eye. Ophthalmoscopy disclosed very mild optic disc pallor in both eyes but no vitreous cells and complete resolution of optic disc edema ( Fig. 7). Humphrey visual fields revealed a mean deviation of 4.4 dB in the right eye and 6.4 dB in the left eye ( Fig. 8). The CRMP- 5 IgG titer had fallen to 1: 30,720. DISCUSSION We have described a patient with PON and vitritis in small cell carcinoma of the lung, a diagnosis not suspected until CRMP- 5, a paraneoplastic antibody associated with this cancer, was discovered. Among the previously reported cases of CRMP- 5- positive PON and vitritis, our case is exceptional in that the CRMP titer was extremely high, yet the patient had no other neurologic abnormalities. Only two cases of CRMP- 5- positive PON have been previously described in which patients lacked other neurologic deficits: in one case, the CRMP- 5 titer was not reported ( 3); in the other, the titer did not change in response to treatment ( 6). Our case is unique in that the patient's CRMP- 5 titer decreased significantly in response to chemotherapy and radiotherapy, a phenomenon not previously described. It is also the only rigorously reported case of resolution of optic nerve swelling and vitritis with normalization of visual acuity after the initiation of chemotherapy and radiotherapy for the underlying cancer. CRMP- associated PON typically presents as subacute visual loss in both eyes with optic disc swelling. PATTERN TION •: • » • • • • • • • • • • • • • • • • • • • • • • • • •: U » U Si • • • • • • £ • S2 • • • a • - - • • • • • • :: • • • • • • • • • • • " ' ' • • • • • • • • * * • • » • • • • FIG. 2. Humphrey visual fields performed at presentation show multiple high thresholds without a localizable configuration to the defect. Mean deviations are - 15 dB in the right eye and - 15.8 dB in the left eye. 18 © 2008 Lippincott Williams & Wilkins Paraneoplastic Optic Neuropathy J Neuro- Ophthalmol, Vol. 28, No. 1, 2008 FIG. 3. Late- phase retinal fluorescein angiography performed at presentation shows bilateral mild optic disc leakage. FIG. 4. Chest CT performed at presentation shows right hilar lymph-adenopathy ( A, arrow) and subcari-nal lymphadenopathy ( B, arrow). FIG. 5. Histopathology of the mediastinal lymph node biopsy. A. High magnification ( X125) hematoxylin and eosin stain shows malignant cells with hyperchromatic irregular nuclei, scant cytoplasm, and nuclear molding. B. CD56 antibody stain for neural cell adhesion molecule has produced diffuse positive brown staining of the cytoplasm of neoplastic cells. 19 J Neuro- Ophthalmol, Vol. 28, No. 1, 2008 Margolin et al FIG. 6. Chest CT performed 5 months after presentation shows a decrease in the size of the hilar lymphadenopathy ( arrow). Vitreous cells are frequently present, as in our patient ( 2,3,7). Most of the previously reported patients, however, differ from ours in having had neurologic accompaniments to their visual loss ( 2,4,5,8). These abnormalities have been divided into two groups ( 2): 1) multifocal encephalomye-loneuropathy ( a cerebellar syndrome being a common finding in this group) and 2) myelitis resembling Devic disease ( 3). As in our patient, the underlying cancer in the vast majority of patients with PON described previously is small cell lung carcinoma ( 2- 5,9,10). However, there are individual case reports of patients with CRMP- 5 PON and bronchial carcinoma, thymoma, thyroid papillary carcinoma, renal cell carcinoma, Hodgkin and non- Hodgkin lymphoma, neuroblastoma, pancreatic glucagonoma, and nasopharyngeal carcinoma ( 4,5,8,9). Interestingly, the patients with a Devic- like presentation have tended to have some of these non- lung cancers ( 2,8,9,11). CRMP- 5 is an IgG antibody first described in 2001 by Yu et al ( 5). Malik et al ( 12) in 1992 had described an antibody in patients with PON that bound only to oligodendrocytes in adult brain. It was later thought to be the same antibody as CRMP- 5. CRMP- 5 is directed against a 62- kDa neuronal cytoplasmic protein of the collapsin response mediator family. It is expressed in adult central and peripheral neurons, in small- cell lung carcinoma, and rarely in thymoma ( 5). The CRMP- 5 family of proteins is believed to mediate growth guidance cues during embryogenesis ( 5). CRMP- 5 IgG is not specific for PON. In a recent paper by Cross et al ( 2), only 16 ( 9%) of 172 patients with positive CRMP- 5 titers had PON; the rest had other neurologic impairments. Up to 35% of patients with positive CRMP- 5 titers and small cell lung carcinomas, however, have some neurologic manifestations such as optic neuropathy/ retinitis with vitreous cells, other cranial neuropathies, and subacute chorea or other basal ganglia disorders ( 2,5,10,13). Other previously described neuro-ophthalmic manifestations have included impaired upgaze, nystagmus, multiple cranial neuropathies, and opsoclonus ( 3,5). The wide variety of other neurologic abnormalities seen in these patients probably results from the effect of the antibodies on many sites in the nervous system ( 2,14). The detection of autoimmune antibodies does not predict a specific neurologic syndrome but rather directs the search toward an underlying cancer, which is present in up to 90% of patients ( 1,2,14). The cancer is often at an early stage and, in some patients is hard to find. In our patient, multiple frozen sections of the lymph nodes obtained by mediastinoscopy were read as a " reactive process" and the diagnosis of sarcoidosis was therefore suggested. Only the knowledge of the very high CRMP- 5 antibody titer persuaded the pathologist to perform additional sectioning and staining that led to the discovery of the underlying FIG. 7. Fundus photography performed 6 months after presentation shows resolution of optic disc edema and vitritis and mild optic disc pallor bilaterally. 20 © 2008 Lippincott Williams & Wilkins Paraneoplastic Optic Neuropathy J Neuro- Ophthalmol, Vol. 28, No. 1, 2008 TIDN » :: •••• s t •••• » B> • • • st u m st » • £ * B FIG. 8. Humphrey visual fields performed 6 months after presentation show improvement with mean deviations of - 4.4 dB in the right eye and - 6.4 dB in the left eye. cancer. Diagnosis and treatment of cancer at this early stage can potentially be curative. It has been hypothesized that the reason for a low tumor burden in these patients is an effective anticancer immune host response ( 1). If true, the use of immunosuppressive medication for the treatment of paraneoplastic disorders might be contraindicated. There is, however, no clinical support for this hypothesis. On the contrary, some patients seem to benefit from immunosuppression with improvement of the paraneoplastic manifestations ( 1,15). Management of a suspected paraneoplastic syndrome should consist of diagnosis and treatment of the underlying cancer together with the use of immunomodulatory therapy ( corticosteroids, intravenous immunoglobulins, and plasmapheresis) in patients who are impaired from the paraneoplastic effects ( 1,15). Immunomodulatory treatment of visual loss in PON has, however, been unrewarding ( 1,18,19). On the basis of very limited success in the treatment of cancer- associated retinopathy ( 16,17), systemic corticosteroids and intravenous immunoglobulins have been tried in PON ( 18,19). Even with simultaneous initiation of chemotherapy and radiotherapy, vision has generally not improved and has often deteriorated ( 2- 4). Our case joins two previously reported cases as exceptions to this experience ( 6,20). One report ( 6) described limited improvement of visual acuity in a patient who was treated with cisplatin and etoposide for underlying small cell lung carcinoma, but the details of the ophthalmic examination were not presented. Another report ( 20) highlighted a substantial improvement in visual function after treatment with intravenous methylprednisolone, cisplatin, and VP- 16, but baseline visual acuities ( 20/ 30 and 20/ 40) were much better than those in our patient and the exact nature of the paraneoplastic antibodies was not determined. PON should be included in the differential diagnosis of any patient presenting with optic nerve swelling and vitritis. Discovery of the CRMP- 5 antibodies can initiate a search for the underlying malignancy while it is at an early stage and lead to the rapid initiation of treatment, which can be potentially curative. Treating the paraneoplastic manifestations with immunomodulatory agents but without anticancer agents may not necessarily be prejudicial toward cancer survival but is unlikely to benefit the paraneoplastic manifestations. REFERENCES 1. Bataller L, Dalmau JO. Paraneoplastic disorders of the central nervous system: update on diagnostic criteria and treatment. Semin Neurol 2004; 24: 461- 7. 2. Cross SA, Salomao DR, Parisi JE, et al. 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, et al. Small cell lung carcinoma presenting as collapsin response- mediating protein ( CRMP)- 5 paraneoplastic optic neuropathy. J Neuroophthalmol 2006; 26: 168- 72. 4. Thambisetty MR, Scherzer CR, Yu Z, et al. Paraneoplastic optic neuropathy and cerebellar ataxia with small cell carcinoma of the lung. J Neuroophthalmol 2001; 21: 164- 7. 5. Yu Z, Kryzer TJ, Griesmann GE, et al. 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