Case Report | Open Access
S. Laroumagne, Xavier Elharrar, B. Coiffard, J. Plojoux, H. Dutau, D. Breen, P. Astoul, "“Dancing Eye Syndrome” Secondary to Opsoclonus-Myoclonus Syndrome in Small-Cell Lung Cancer", Case Reports in Medicine, vol. 2014, Article ID 545490, 4 pages, 2014. https://doi.org/10.1155/2014/545490
“Dancing Eye Syndrome” Secondary to Opsoclonus-Myoclonus Syndrome in Small-Cell Lung Cancer
Among paraneoplastic neurologic disorders (PND), opsoclonus-myoclonus syndrome, so-called “dancing eye syndrome,” is a rare disorder combining multivectorial eye movements, involuntary multifocal myoclonus, and cerebellar ataxia. Although several paraneoplastic antibodies against postsynaptic or cell-surface antigens have been reported, usually most patients are serum antibody negative. We report a 65-year-old patient with opsoclonus-myoclonus syndrome revealing a small-cell lung carcinoma. If serologic antineuronal anti-body screening was negative, autoantibodies against glutamic acid decarboxylase (anti-GAD) were positive. Despite the specific anticancer treatment and high dose corticosteroids, the patient developed a severe and progressive encephalopathy and died 10 days later.
Opsoclonus-myoclonus syndrome (OMS) is characterized by rapid, involuntary multivectorial eye movements without intersaccadic intervals. It is associated with involuntary multifocal myoclonus mainly affecting the trunk, limbs, and head. Cerebellar ataxia and uncoordinated voluntary movements may also be seen. Pathophysiologically OMS appears to be an immune-mediated disease where positive titres directed at anti-neuronal antibodies in the serum and cerebrospinal fluid (CSF) are occasionally detected. OMS has been linked to infections and metabolic disorders and has been documented as a paraneoplastic syndrome.
The paraneoplastic opsoclonus-myoclonus syndrome, also called “dancing eyes syndrome,” is a rare entity among the paraneoplastic neurologic disorders (PND) . OMS is mainly associated with neuroblastoma in children; however, it has also been reported in patients with small-cell lung cancer (SCLC) and breast and ovarian malignancies. In addition, there have been case reports in the literature which have associated OMS with non-small-cell lung cancer, melanoma, sarcoma, and non-Hodgkin’s lymphoma [2–5].
In this paper, we report the case of a male patient with pathologically proven small-cell lung cancer who presented with symptoms compatible with OMS. This was the first clinical manifestation of an underlying malignancy. He demonstrated a rapid deterioration in his clinical state leading to death despite the introduction of chemotherapy active against the small-cell lung cancer.
2. Case Report
A 65-year-old man presented to the emergency department of our institution with a history of left hemithoracic pain, weight loss, gait ataxia, and tremor. He had a 120-pack-year smoking history and known ischemic cardiomyopathy with previous coronary stenting.
On physical examination he had a reduced performance status (PS 1, ECOG classification) and neurological assessment revealed tremor, gait ataxia, and mild involuntary limb jerking which resulted in the patient remaining bedbound despite any evidence of cognitive impairment and sensory or motor deficit. The initial chest X-ray demonstrated an enlarged left hilum. Thoracic imaging by computed tomography (CT) revealed a left hilar mass measuring 26 mm with associated left hilar and mediastinal lymphadenopathy (>1 cm short axis) (Figure 1). Endobronchial ultrasound (EBUS) and transbronchial needle aspiration (TBNA) of the involved lymph nodes were performed and this confirmed a diagnosis of small-cell lung cancer (SCLC). The diagnostic workup was completed with 18-fluorodeoxyglucose-positron emission tomography (18-FDG-PET) which staged the SCLC as limited disease.
Further workup for a potential cerebellar paraneoplastic disorder revealed a normal electroencephalography, normal cell counts, protein levels, viral markers, and negative cytology in the cerebrospinal fluid (CSF) analysis. Magnetic resonance imaging (MRI) of the brain did not reveal ischemic changes, metastatic lesions, or abnormal enhancement with gadolinium (Figure 2). Brain 18-FDG-PET demonstrated diffuse cerebral hypometabolism with cerebellar hypermetabolism which is a reported finding in PND (Figure 3).
As the index of suspicion for PND remained high, we performed serologic anti-neuronal antibody screening. Anti-Hu, Ant-Ri, anti-Yo, anti-CV2, anti-Ma1, anti-Ma2, anti-amphiphysin, and anti-VGKC were all negative. A serum glutamic acid decarboxylase antibody radio immunoassay (GAD65 Ab Assay—AntiGAD Antibodies blood test) was positive (1.1 U/mL) (Titers generally < or = 0.03 U/L).
Chemotherapy was commenced using the combination of carboplatinum and etoposide with intravenous corticosteroids. Cisplatinum administration was contraindicated because of the recent history of ischemic cardiomyopathy and a measured ventricular ejection fraction at 40%. Despite the initiation of specific treatment of the underlying malignancy, dramatic neurologic deterioration occurred and the patient developed multivectorial saccadic eye movements with associated massive myoclonic head, trunk, and limb movements. This deterioration resulted in a comatose state necessitating endotracheal intubation, sedation, and transfer to the intensive care unit.
The patient died 10 days later due to severe and progressive encephalopathy despite the specific anticancer treatment and high dose corticosteroids.
Paraneoplastic OMS has been associated with SCLC and breast and ovarian malignancies in adults and antineuronal antibodies have been occasionally detected [6, 7]. Among the anti-neuronal antibodies, anti-RI, a nonsurface antigen type, Zic2 antigen (anti-Zic2), and more recently adenomatous polyposis coli antigen (anti-APC) are the most frequently detected [7, 8]. The enzyme called glutamic acid decarboxylase is responsible for converting glutamic acid to GABA which is found in the cerebellum. For some authors cerebellar ataxia and other cerebellar disorders should be the result of a lack of GABA which is targeted by anti-GAD antibodies. Patients with cerebellar ataxia of an unknown cause should have an anti-GAD test . Nevertheless, the majority of patients with PND and OMS are antibody negative; however, this does not exclude the diagnosis.
OMS is an involuntary multidirectional eye movement syndrome (spontaneous conjugate saccades in all directions of gaze) accompanied by myoclonic jerks (irregular muscle spasms of the head, trunk, or extremities). Cerebellar ataxia (POMA syndrome), tremor, and encephalopathy are common. As with the majority of PND, OMS precedes the diagnosis of cancer (in up to two-thirds of cases), but it can also be detected during the follow-up period suggesting recurrent disease . The pathophysiological mechanism is still unclear. Some researchers suggest disinhibition of cerebellar nuclei or dysfunction of premotor neurons of the brainstem [10, 11].
In our case the patient initially presented with cerebellar symptoms. Investigations were consistent with a cerebellar paraneoplastic disorder supported by a histologically proven diagnosis of SCLC, brain 18-FDG-PET findings, and positive anti-GAD antibodies [12, 13]. Our patient showed hypermetabolism in the cerebellum on FDG-PET scan. The hypermetabolism should be related to inflammatory changes as previously shown in the literature when stereotaxic biopsy is done revealing lymphocytic infiltrations and reactive gliosis  or at autopsy studies with severe loss of Purkinje cells in combination with various degrees of inflammatory . Conversely studies performed more than 1 year after the onset of symptoms consistently show absence of inflammatory infiltrates (hypometabolism at FDG-PET) suggesting the regression of inflammatory process .
The rapid progression towards OMS with multidirectional eye movements and jerking body movements and ultimately coma strongly suggests a paraneoplastic phenomenon, even if standard serological screening for anti-neuronal antibodies associated with OMS remained negative. It is therefore not surprising that current recommendations are to repeat the screening tests every six months if malignancy is not initially discovered . However, reports in the literature suggest that up to 50% of patients have improvement in their neurologic function and the prognosis in small-cell lung cancer patients is better if associated with positive neuronal antibodies tests .
In summary we believe that new approaches to detect anti-neuronal antibodies will allow faster detection of the underlying malignancy of PND leading to an earlier treatment of the disease with better outcomes for the patients.
Conflict of Interests
The authors declare that there is no conflict of interests regarding the publication of this paper.
- J. Dalmau and M. R. Rosenfeld, “Paraneoplastic syndromes of the CNS,” The Lancet Neurology, vol. 7, no. 4, pp. 327–340, 2008.
- K. Musunuru and S. Kesari, “Paraneoplastic opsoclonus-myoclonus ataxia associated with non-small-cell lung carcinoma,” Journal of Neuro-Oncology, vol. 90, no. 2, pp. 213–216, 2008.
- J. R. Berger and E. Mehari, “Paraneoplastic opsoclonus-myoclonus secondary to malignant melanoma,” Journal of Neuro-Oncology, vol. 41, no. 1, pp. 43–45, 1999.
- J. Hauspy, A. Nevin, I. Harley et al., “Paraneoplastic syndrome in vaginal melanoma: a case report and review of the literature,” International Journal of Gynecological Cancer, vol. 17, no. 5, pp. 1159–1163, 2007.
- A. Kumar, W. A. Lajara-Nanson, and R. W. Neilson Jr., “Paraneoplastic Opsoclonus-Myoclonus Syndrome: initial presentation of non-Hodgkins lymphoma,” Journal of Neuro-Oncology, vol. 73, no. 1, pp. 43–45, 2005.
- E. Dropcho and R. Payne, “Paraneoplastic opsoclonus-myoclonus: association with medullary thyroid carcinoma and review of the literature,” Archives of Neurology, vol. 43, no. 4, pp. 410–415, 1986.
- S. J. Pittock, C. F. Lucchinetti, and V. A. Lennon, “Anti-neuronal nuclear autoantibody type 2: paraneoplastic accompaniments,” Annals of Neurology, vol. 53, no. 5, pp. 580–587, 2003.
- L. Bataller, M. R. Rosenfeld, F. Graus, J. J. Vilchez, N.-K. V. Cheung, and J. Dalmau, “Autoantigen diversity in the opsoclonus-myoclonus syndrome,” Annals of Neurology, vol. 53, no. 3, pp. 347–353, 2003.
- E. Nadal, J. Bruna, M. O. de Olza, M. Antonio, and F. Cardenal, “Paraneoplastic opsoclonus-myoclonus syndrome as a new and single manifestation of relapsing disease in a patient with small cell lung cancer,” Journal of Thoracic Oncology, vol. 6, no. 5, pp. 968–969, 2011.
- C. Helmchen, H. Rambold, A. Sprenger, C. Erdmann, and F. Binkofski, “Cerebellar activation in opsoclonus: an fMRI study,” Neurology, vol. 61, no. 3, pp. 412–415, 2003.
- K. M. Vandervest and M. I. Schwarz, “A 76-year-old woman with acute CNS symptoms and pulmonary nodules,” Chest, vol. 136, no. 6, pp. 1686–1689, 2009.
- A. Saiz, Y. Blanco, L. Sabater et al., “Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association,” Brain, vol. 131, no. 10, pp. 2553–2563, 2008.
- J. C. McHugh, B. Murray, R. Renganathan, S. Connolly, and T. Lynch, “GAD antibody positive paraneoplastic stiff person syndrome in a patient with renal cell carcinoma,” Movement Disorders, vol. 22, no. 9, pp. 1343–1346, 2007.
- R. Scheid, T. Lincke, R. Voltz, D. Y. von Cramon, and O. Sabri, “Serial 18F-fluoro-2-deoxy-D-glucose positron emission tomography and magnetic resonance imaging of paraneoplastic limbic encephalitis,” Archives of Neurology, vol. 61, no. 11, pp. 1785–1789, 2004.
- B. Giometto, G. C. Marchiori, P. Nicolao et al., “Sub-acute cerebellar degeneration with anti-Yo autoantibodies: immunohistochemical analysis of the immune reaction in the central nervous system,” Neuropathology and Applied Neurobiology, vol. 23, no. 6, pp. 468–474, 1997.
- J. Verschnuren, L. Chuang, M. K. Rosenblum et al., “Inflammatory infiltrates and complete absence of Purkinje cells in anti-Yo-associated paraneoplastic cerebellar degeneration,” Acta Neuropathologica, vol. 91, no. 5, pp. 519–525, 1996.
- C. A. Vedeler, J. C. Antoine, B. Giometto et al., “Management of paraneoplastic neurological syndromes: report of an EFNS Task Force,” European Journal of Neurology, vol. 13, no. 7, pp. 682–690, 2006.
- M. J. Titulaera, R. Soffiettib, J. Dalmauc et al., “Screening for tumours in paraneoplastic syndromes: report of an EFNS Task Force,” European Journal of Neurology, vol. 18, no. 1, p. 19-e3, 2011.
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