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Show ORIGINAL CONTRIBUTION Long- Term Survival in Paraneoplastic Opsoclonus- Myoclonus Syndrome Associated With Small Cell Lung Cancer Khaled A. Hassan, MD, Gregory P. Kalemkerian, MD, and Jonathan D. Trobe, MD Abstract: Paraneoplastic opsoclonus- myoclonus syndrome ( OMS) is associated with small cell lung cancer ( SCLC) in adults. Without appropriate treatment for SCLC, all reported patients with SCLC and OMS have died of complications of OMS within 3 months of diagnosis. With appropriate treatment, about half of reported patients have had improvement in neurologic function, and several have become long- term survivors ( 6- 84 months). We report a patient with SCLC who presented with OMS and was refractory to immunosuppressive therapy but responded rapidly to antineoplastic therapy and remains alive with no sign of SCLC recurrence and minimal residual neurologic deficits 30 months after diagnosis. In patients presenting with OMS, early recognition and treatment of the underlying malignancy probably improve the chances for recovery from the OMS with minimal deficit and ultimate survival. (/ Neuro- Ophthalmol 2008; 28: 27- 30) Small cell lung cancer ( SCLC) is a poorly differentiated neuroendocrine malignancy characterized by aggressive growth and early metastases. It accounts for 15%- 20% of all cases of lung cancer ( 1). Most patients with SCLC present with extensive- stage disease for which chemotherapy is associated with prolongation of survival, but rarely beyond 2 years. One third of patients with SCLC present with limited- stage disease, denned as disease confined to the ipsilateral hemithorax and mediastinum that can be safely encompassed within one radiation field. In limited-stage SCLC, the goal of treatment is cure. Concurrent Departments of Medicine ( KAH, GPK) and Ophthalmology, Neurology, and Neurosurgery ( JDT), University of Michigan, Ann Arbor, Michigan. Supplementary video is available online at www. jneuro-ophthalmology. com. Address correspondence to Gregory P. Kalemkerian, MD, C350 Med Inn Building, 0848 1500 E. Medical Center Dr., Ann Arbor, MI 48109- 0848; E- mail: kalemker@ umich. edu administration of platinum- based chemotherapy and radiotherapy results in a 5- year survival rate of 20%- 25% ( 2,3). The neuroendocrine nature of SCLC accounts for its association with a variety of endocrine and neurologic paraneoplastic syndromes ( PNSs). Endocrine PNSs such as syndrome of inappropriate antidiuretic hormone ( SIADH) and Cushing syndrome are caused by ectopic secretion of peptide hormones by SCLC cells and are reversible with appropriate anti- cancer therapy. In contrast, neurologic PNSs are caused by an autoimmune response to specific antigens expressed on cancer cells, leading to the production of autoantibodies that cross- react with specific components of the nervous system ( 4,5). Frequently, these autoantibodies induce neuronal cell death, resulting in progressive and irreversible neurologic dysfunction such as that seen in limbic encephalopathy and subacute cerebellar degeneration. Some autoantibodies merely interfere with neurologic signaling, a derangement that can be successfully reversed with immunosuppression or antineoplastic therapy, as is the case in Lambert- Eaton myasthenic syndrome. Opsoclonus- myoclonus syndrome ( OMS), a rare disorder that is frequently associated with malignancy, is characterized by opsoclonus ( spontaneous, arrhythmic, large- amplitude, conjugate saccades occurring in all directions of gaze) and myoclonus ( irregular muscular spasms of the head, trunk, or extremities) and sometimes encephalopathy ( 6). The pathophysiologic basis of OMS is unknown. Neuronal cell loss has not been identified and, in some patients, the clinical manifestations appear to be reversible. It has been suggested that OMS may be due to a disturbance in the inhibitory neurotransmitter system caused by anti- glycine receptor autoantibodies. Sera from patients with paraneoplastic OMS can disrupt the binding of Nova- l/ Nova- 2 proteins to glycine receptor mRNA, causing deregulation of its expression that may explain the underlying motor dysfunction of OMS ( 7,8). Long- term survival of patients with SCLC and paraneoplastic OMS ranges from 6 to 84 months ( 9,10). We describe a patient with SCLC and OMS who was treated 27 J Neuro- Ophthalmol, Vol. 28, No. 1, 2008 Hassan et al with appropriate anti- cancer therapy and remains cancer- free 30 months after diagnosis without significant neurologic sequelae, joining a small number of reported OMS/ SCLC patients with neurologic recovery and long- term survival. CASE REPORT A 57- year- old woman developed diplopia, dysarthria, and involuntary motor activity involving her eyes, head trunk, and extremities. She was a long- time smoker. Results of brain MRI and electroencephalography were normal. Results of standard blood and serum evaluation and lumbar puncture were unrevealing. CT of the chest, abdomen, and pelvis revealed a 1.5- cm left hilar mass. After 5 weeks of progressive symptoms, she developed respiratory failure requiring mechanical ventilation. Upon arrival at our institution, she did not respond to verbal stimuli but did withdraw to pain. She had spontaneous random jerking movements of the face, head and all four extremities. Rapid, random, conjugate eye movements in all directions were noted under closed lids and were present when her eyelids were lifted ( see Video, available online- only through ArticlePlus). The right eye was consistently higher than the left eye ( attributed to skew deviation). Results of pupil and optic fundus examinations were normal. Deep tendon reflexes were intact, and plantar reflexes were flexor. We made a clinical diagnosis of paraneoplastic OMS, but results of a comprehensive paraneoplastic antibody panel ( Mayo Clinic) were negative. She was treated with intravenous immunoglobulin ( IVIg) ( 1 g/ kg initial dose followed by 0.5 g/ kg) for 10 days and 1 g methylprednis-olone intravenously daily for 5 days followed by 60 mg prednisone daily for 8 days without clinical improvement. A chest CT repeated 13 days after the initial study showed enlargement of the left hilar mass to 2.5 cm ( Fig. 1). Bronchoscopic aspiration biopsy of this mass revealed FIG. 1. Chest CT shows a 2.5- cm left hilar mass { arrow) with small bilateral pleural effusions. SCLC ( Fig. 2). Results of immunohistochemical analysis were positive for pancytokeratin and CD56 ( neural cell adhesion molecule), and negative for leukocyte common antigen. Positron emission tomography with fluorodeox-yglucose showed uptake only in the biopsied left hilar mass. She was treated with carboplatin and etoposide. Two days later, myoclonus was markedly improved and she was extubated. After a second cycle of chemotherapy, she was discharged from the hospital with normal mental status, no myoclonus, and minimal opsoclonus. She completed four cycles of chemotherapy followed by thoracic radiotherapy for limited- stage SCLC with complete tumor response and resolution of neurologic signs and symptoms by the end of treatment. Thirty months after her initial diagnosis, she remains cancer- free, and her only residual neurologic symptom is mild tandem gait instability accentuated by fatigue. DISCUSSION Paraneoplastic OMS is most commonly associated with neuroblastoma in children and with SCLC in adults ( 11,12). However, it has been reported in association with cancers of the ovary, breast, thyroid gland, and kidney and with Hodgkin and non- Hodgkin lymphoma and melanoma ( 6,13- 17). Paraneoplastic OMS is thought to be antibody mediated. In a study of children with neuroblastoma, those with OMS had significantly higher serum titers of anti- neuronal antibodies ( 18). The presence of numerous 28 © 2008 Lippincott Williams & Wilkins Paraneoplastic Opsoclonus- Myoclonus J Neuro- Ophthalmol, Vol. 28, No. 1, 2008 anti- neural antibodies, including anti- Hu, anti- Ri, anti-neurofilament, and anti- Purkinje cell antibodies, has been described in patients with paraneoplastic OMS, but none of these has been consistently associated with the clinical syndrome ( 19- 22). Patients with neuroblastoma- associated OMS also exhibit elevated numbers of B lymphocytes in the CSF as well as interstitial or perivascular lymphoid infiltrates containing follicular dendritic cells and B lymphocytes, suggesting a localized immune reaction that can result in antibody production ( 23,24). Despite evidence of an autoimmune etiology for OMS and the lack of evidence of neuronal cell death on autopsy studies, immunosuppressive therapy with adrenocorticotropic hormone ( ACTH), corticosteroids, IVlg, cyclophosphamide, azathioprine, and plasmapheresis has produced inconsistent clinical improvement ( 25,26). Clinical improvement has, however, been reported with rituximab, a monoclonal antibody targeting CD20- expressing B lymphocytes ( 27). It appears that tumor control is essential for successful long- term management of paraneoplastic OMS. In a series of 14 patients with OMS associated with a variety of tumor types, 6 were treated with IVlg and/ or corticosteroids without antineoplastic therapy, whereas the remaining 8 received appropriate treatment for their primary malignancies ( 9). Five of the 6 patients treated with immunosuppression alone died of progressive OMS within 6 months, whereas the 8 patients who received appropriate anti- cancer therapy all had complete or partial neurologic improvement and only 2 died of progressive malignancy at 11 and 18 months after diagnosis. The remaining 6 patients are alive with follow- up ranging from 6 months to 14 years. Survival of patients with paraneoplastic OMS varies considerably, depending on the underlying malignancy, but appears to be longer in patients with potentially curable cancers. A relatively long survival rate has been reported in children with neuroblastoma and paraneoplastic OMS compared with children with neuroblastoma unassociated with OMS ( 28). Korfei et al ( 29) reported that serum from patients with OMS can inhibit cellular proliferation and induce apoptosis in neuroblastoma cell lines, suggesting that OMS- associated autoantibodies may confer an antineoplastic benefit in patients with neuroblastoma. However, there are no clinical or laboratory data to support such an effect in adult patients with paraneoplastic OMS associated with other tumors. There have been 18 cases of OMS associated with SCLC reported in the English literature since 1990 ( 9,10, 30- 33). Treatment and survival data are available for 15 of these patients ( Table 1). Of the 4 patients who did not receive anti- cancer therapy, 3 died of progression of neurologic symptoms within 3 months of diagnosis and 1 died within 5 months with no available cause of death. Of the 11 patients who received anti- cancer therapy, all had substantial improvement of neurologic symptoms. One patient had TABLE 1. Cases of paraneoplastic opsoclonus- myoclonus syndrome associated with small cell lung cancer Author Hersh et al ( 30) Nitschke et al ( 31) Bataller et al ( 9) Pittock et al ( 10) Blaes et al ( 32) Ohara et al ( 33) Current report Immune - + + - - + - + + + + - + + - + Treatment Anti- Tumor - + - + + + + + + - - + + + + + Neurologic status Worse Improved Worse No residual deficits Mild truncal ataxia Mild truncal ataxia Mild truncal ataxia Mild truncal ataxia Mild truncal ataxia Worse Worse Ataxia and mild opsoclonus Worse Mild truncal ataxia Truncal ataxia and cognitive deficits Mild gait disorder Survival status ( months) Dead ( 5) Dead ( 4) Dead ( 1) Alive ( 17) Dead ( 22) Dead ( 11) Dead ( 18) Alive ( 39) Alive ( 6) Dead ( 3) Dead ( 3) Alive ( 84) Dead ( 3) Alive ( 24) Dead ( 35) Alive ( 30) reported since 1990 Cause of death Unknown SCLC Encephalopathy SCLC SCLC SCLC Encephalopathy Encephalopathy Unknown Sepsis SCLC, small cell lung cancer. 29 J Neuro- Ophthalmol, Vol. 28, No. 1, 2008 Hassan et al complete resolution of neurologic symptoms and remains alive and asymptomatic 17 months after appropriate anticancer therapy ( 9). Among the remaining 10 patients, 4 remain alive with residual mild neurologic deficits at follow-up ranging from 6 to 84 months, whereas 6 have died, 4 from progressive SCLC ( 4, 11,18, and 22 months), 1 from sepsis ( 35 months), and 1 of an unknown cause ( 3 months). Thus, before the report of our patient, there had been 5 instances of long- term survival in patients with OMS associated with SCLC reported since 1990. The longest survivor was cancer- free with residual truncal ataxia and mild opsoclonus 84 months after diagnosis ( 10). The other four patients were alive for 6, 17, 24, and 39 months after diagnosis ( 9,32). Another patient died 35 months after diagnosis of complications of persistent neurologic debility ( 33). Overall, only 3 patients with OMS associated with SCLC have been reported to have a survival time longer than that of our patient, who is alive with a mild tandem gait disorder 30 months after diagnosis. 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