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Original Investigation |

Clinical and Immunological Features of Opsoclonus-Myoclonus Syndrome in the Era of Neuronal Cell Surface Antibodies

Thaís Armangué, MD, PhD1; Lidia Sabater, PhD1; Estefanía Torres-Vega, BSc2; Eugenia Martínez-Hernández, MD, PhD1; Helena Ariño, MD1; Mar Petit-Pedrol, BSc1; Jesús Planagumà, PhD1; Luis Bataller, MD, PhD2; Josep Dalmau, MD, PhD1,3,4; Francesc Graus, MD, PhD1,5
[+] Author Affiliations
1Neuroimmunology Program, Institut d’Investigació Biomèdica August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
2Service of Neurology, University Hospital Politècnic La Fe, Valencia, Spain
3Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
4Department of Neurology, University of Pennsylvania, Philadelphia
5Service of Neurology, Hospital Clínic, Barcelona, Spain
JAMA Neurol. 2016;73(4):417-424. doi:10.1001/jamaneurol.2015.4607.
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Importance  Most studies on opsoclonus-myoclonus syndrome (OMS) in adults are based on small case series before the era of neuronal cell surface antibody discovery.

Objective  To report the clinical and immunological features of idiopathic OMS (I-OMS) and paraneoplastic OMS (P-OMS), the occurrence of antibodies to cell surface antigens, and the discovery of a novel cell surface epitope.

Design, Setting, and Participants  Retrospective cohort study and laboratory investigations of 114 adult patients with OMS at a center for autoimmune neurological disorders done between January 2013 and September 2015.

Main Outcomes and Measures  Review of clinical records. Immunohistochemistry on rat brain and cultured neurons as well as cell-based assays were used to identify known autoantibodies. Immunoprecipitation and mass spectrometry were used to characterize novel antigens.

Results  Of the 114 patients (62 [54%] female; median age, 45 years; interquartile range, 32-60 years), 45 (39%) had P-OMS and 69 (61%) had I-OMS. In patients with P-OMS, the associated tumors included lung cancer (n = 19), breast cancer (n = 10), other cancers (n = 5), and ovarian teratoma (n = 8); 3 additional patients without detectable cancer were considered to have P-OMS because they had positive results for onconeuronal antibodies. Patients with I-OMS, compared with those who had P-OMS, were younger (median age, 38 [interquartile range, 31-50] vs 54 [interquartile range, 45-65] years; P < .001), presented more often with prodromal symptoms or active infection (33% vs 13%; P = .02), less frequently had encephalopathy (10% vs 29%; P = .01), and had better outcome (defined by a modified Rankin Scale score ≤2 at last visit; 84% vs 39%; P < .001) with fewer relapses (7% vs 24%; P = .04). Onconeuronal antibodies occurred in 13 patients (11%), mostly Ri/ANNA2 antibodies, which were detected in 7 of 10 patients (70%) with breast cancer. Neuronal surface antibodies were identified in 12 patients (11%), mainly glycine receptor antibodies (9 cases), which predominated in P-OMS with lung cancer (21% vs 5% in patients with OMS without lung cancer; P = .02); however, a similar frequency of glycine receptor antibodies was found in patients with lung cancer without OMS (13 of 65 patients [20%]). A novel cell surface epitope, human natural killer 1 (HNK-1), was the target of the antibodies in 3 patients with lung cancer and P-OMS.

Conclusions and Relevance  Patients with I-OMS responded better to treatment and had fewer relapses than those with P-OMS. Older age and encephalopathy, significantly associated with P-OMS, are clinical clues suggesting an underlying tumor. Glycine receptor antibodies occur frequently in P-OMS with lung cancer, but the sensitivity and specificity are low. The HNK-1 epitope is a novel epitope in a subset of patients with P-OMS and lung cancer.

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Figure 1.
Immunostaining Results on Frozen Sections of Rat Brain

A-C, Immunoreactivity developed with standard avidin-biotin immunoperoxidase technique. A, Cerebrospinal fluid immunoreactivity from 1 of the 3 patients with paraneoplastic opsoclonus-myoclonus syndrome (P-OMS), lung cancer, and IgM antibodies against an unknown antigen (original magnification ×40). Inset, Higher-magnification image (original magnification ×400). B, This pattern of immunostaining was similar to that seen in patients with polyneuropathy and IgM myelin-associated glycoprotein (MAG) antibodies targeting glycosylated human natural killer 1 (HNK-1) epitopes. Note the high similarity in the staining surrounding the neuronal cell bodies and along proximal dendrites of large neurons (original magnification ×40). Inset, Higher-magnification image (original magnification ×400). C, The absence of reactivity in the cerebrospinal fluid of a control (original magnification ×40).

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Figure 2.
Immunoblot Results

Immunoblot of human myelin proteins probed with serum of a patient with IgM myelin-associated glycoprotein antibodies and neuropathy (lane 1), a commercial antibody against human natural killer 1 (HNK-1) (lane 2), and the cerebrospinal fluid of our 3 patients with paraneoplastic opsoclonus-myoclonus syndrome and lung cancer (lanes 3-5). Note that all patient and commercial antibodies reacted with bands of similar molecular weight that are not shown by the negative control sample (lane 6).

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Figure 3.
Immunofluorescence Results

Immunofluorescence on live hippocampal neurons incubated with the cerebrospinal fluid of 1 of the 3 patients with paraneoplastic opsoclonus-myoclonus syndrome (P-OMS), lung cancer, and IgM antibodies (A-D) and the serum of a patient with polyneuropathy and IgM myelin-associated glycoprotein (MAG) antibodies (E-H). The punctate IgM immunoreactivity of the 2 patients (A and E) colocalized with the reactivity of a commercial antibody against human natural killer 1 (HNK-1) (B and F), shown in the merged images (C and G); a high degree of colocalization was confirmed by Imaris software (Mander coefficient = 0.8 for both fluorescent channels; the coefficient ranges from 0.0 [no colocalization] to 1.0 [full colocalization]19) (D and H) (scale bar = 20 μm).

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Figure 4.
Immunoblot Results of the Immunoprecipitated Proteins

To determine whether the immunoprecipitated antigen was the glutamate receptor 2 (GluR2) subunit, immunoblots of neuronal proteins precipitated with cerebrospinal fluid from patients with paraneoplastic opsoclonus-myoclonus syndrome and IgM human natural killer 1 antibodies were probed with commercial antibodies against the GluR2 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) (lane 1) and a monoclonal human natural killer 1 antibody (lane 2). Both antibodies recognize a similar band in the 98-kDa range consistent with GluR2. This band was not observed in immunoblots of neuronal proteins precipitated with a control’s cerebrospinal fluid probed with the same antibodies against GluR2 (lane 3) and human natural killer 1 (lane 4).

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