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Neuronal surface antigen antibodies in limbic encephalitis

Clinical–immunologic associations

From the Service of Neurology (F.G., A.S., F.L., L.S., Y.B.), Hospital Clinic and Institut d’ Investigació Biomèdica August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Department of Neurology (M.L., J.D.), University of Pennsylvania, Philadelphia; Service of Neurology (J.B.), C.S.U. Bellvitge, Hospitalet, Spain; and Brain Tissue Bank (M.J.R., T.R.), University of Barcelona, Hospital Clínic, Spain.

Address correspondence and reprint requests to Dr. Francesc Graus, Servei de Neurologia, Hospital Clínic, Villarroel 170, Barcelona 08036, Spain fgraus{at}clinic.ub.es

Objective: To report the frequency and type of antibodies against neuronal surface antigens (NSA-ab) in limbic encephalitis (LE).

Methods: Analysis of clinical features, neuropathologic findings, and detection of NSA-ab using immunochemistry on rat tissue and neuronal cultures in a series of 45 patients with paraneoplastic (23) or idiopathic (22) LE.

Results: NSA-ab were identified in 29 patients (64%; 12 paraneoplastic, 17 idiopathic). Thirteen patients had voltage-gated potassium channels (VGKC)-ab, 11 novel NSA (nNSA)-ab, and 5 NMDA receptor (NMDAR)-ab. nNSA-ab did not identify a common antigen and were more frequent in paraneoplastic than idiopathic LE (39% vs 9%; p = 0.03). When compared with VGKC-ab or NMDAR-ab, the nNSA associated more frequently with intraneuronal antibodies (11% vs 73%; p = 0.001). Of 12 patients (9 nNSA-ab, 2 VGKC-ab, 1 NMDAR-ab) with paraneoplastic LE and NSA-ab, concomitant intraneuronal antibodies occurred in 9 (75%). None of these 12 patients improved with immunotherapy. The autopsy of three of them showed neuronal loss, microgliosis, and cytotoxic T cell infiltrates in the hippocampus and amygdala. These findings were compatible with a T-cell mediated neuronal damage. In contrast, 13 of 17 (76%) patients with idiopathic LE and NSA-ab (8 VGKC-ab, 4 NMDAR-ab, 1 nNSA-ab) and 1 of 5 (20%) without antibodies had clinical improvement (p = 0.04).

Conclusions: In paraneoplastic limbic encephalitis (LE), novel antibodies against neuronal surface antigens (nNSA-ab) occur frequently, coexist with antibodies against intracellular antigens, and these cases are refractory to immunotherapy. In idiopathic LE, the likelihood of improvement is significantly higher in patients with NSA-ab than in those without antibodies.

GLOSSARY: GAD = glutamic acid decarboxylase; LE = limbic encephalitis; NMDAR = N-methyl-D-aspartate receptor; NSA = neuronal surface antigens; nNSA = novel NSA; SCLC = small-cell lung cancer; VGKC = voltage-gated potassium channels; WBC = white blood cells.

Supplemental data at www.neurology.org

Supported in part by grants PI030028 Fondo de Investigaciones Sanitarias, Madrid, Spain (F.G.), and National Cancer Institute/National Institute of Health, RO1CA107192 (J.D.).

Disclosure: The authors report no disclosures.

Received March 29, 2008. Accepted in final form June 13, 2008.